Substituted quinazoline and pyrido-pyrimidine derivatives

ABSTRACT

The present application provides novel substituted quinazoline and pyrido-pyrimidine compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating PI3K and/or mTOR activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the PI3K/AKT/mTOR pathway. Advantageously, these compounds perform as dual PI3K/mTOR inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the priorities of U.S.Provisional Patent Application No. 61/408,620, filed Oct. 31, 2010 andU.S. Provisional Patent Application No. 61/501,901, filed Jun. 28, 2011.These priority applications are herein incorporated by reference.

BACKGROUND

With the onset of cancers which are refractory to most conventionaltreatments, there is a need for new and effective chemotherapeutics. Asdetails emerge about the molecular etiology of various cancers, newchemotherapeutics can be designed which affect one or more vulnerabletargets associated with a given cancer at a sub-cellular level.

Certain cancers (and indeed other diseases of abnormal cellular growth)include those which are due to the dysregulation of one particularmolecular signaling pathway in the body. Restoring regulation of thatparticular pathway to normal or near-normal levels can have a positiveimpact in treating the patient, including a reduction in tumor size oreven putting the patient into remission.

For example, perturbations of the phosphoinositide 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway areclosely associated with the etiology of most solid tumors. ThePI3K/AKT/mTOR pathway can be overactivated by a number of moleculareffectors, including chemokines, the loss of INPP4B or PTEN expression,or by mutations in PI3K itself. Overactivation of this pathway canmanifest in a number of molecular and morphological changes which arecharacteristic of tumorigenesis, including increased cell proliferation,survival and motility, and altered cell cycle entry. mTOR is a centralregulator of cell growth which acts by controlling cellular proteintranslation. Several small molecules have been described as being mTORinhibitors which are useful for treating cancers. PI3K is aheterodimeric enzyme that generates lipid second messengers, such asphosphatidylinositol-3,4,5-triphosphate (PIP3), that mediate signaltransduction. PI3K enzymes regulate key signal transduction pathwayscontrolling vital cell processes that are implicated in carcinogenesis,and include four isoforms; i.e., p110α, p110β, p110δ and p110γ. Specificmutations in p110α have been identified in various cancers. Severalsmall molecules have been described as inhibitors of PI3K. Further,there are a number of compounds, including wortmannins and rapamycins,which have been shown to be highly potent and specific inhibitors ofPI3K and mTOR, respectively.

Indeed, several recent compounds have been described as being useful inregulating the PI3K/mTOR pathway. For example, GDC-0941, PX-866, XL-147,BKM-120, and BAY 80-6946 are inhibitors of PI3K, whereas rapamycin,temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (deforolimus,AP23573, MK-8669), OSI-027 and AZD8055 are inhibitors of mTOR. However,intervention at a single point in a the PI3K/AKT/mTOR signaling pathwaymay not be as effective in treating solid tumors as targeting multiplepathway members. Administering multiple drugs to a cancer patient, eachof which inhibit a certain target in the PI3K or mTOR pathway, carriesits own risks in terms of increased drug load, potential toxicity,drug-drug interactions and the like. What remains in the art, therefore,is the need for single compounds which regulate the PI3K/AKT/mTORpathway by targeting both PI3K and mTOR. Certain compounds recentlydescribed in the art, including BEZ-235, XL-765, GDC-0980, GSK-2126458,PKI-587, and PF-04691502, have been reported to target both PI3K andmTOR. However, the need remains for compounds with this type of dualactivity profile to be developed and approved for clinical use.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I),wherein R¹-R⁶, A, X, Y, Z, and M are defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound of formula(IA), wherein R¹-R⁸, A, X, Y, and Z are defined herein, or apharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a compound offormula (IB), wherein R¹-R⁶, R⁹, R¹⁰, A, X, Y, and Z are defined herein,or a pharmaceutically acceptable salt or solvate thereof.

In still another aspect, compounds of formulae (II)-(XVIII) areprovided, wherein R¹-R³, R⁵-R⁸, M are defined herein.

In yet another aspect, the invention provides a pharmaceuticalcomposition comprising a compound of any of formula (I) to (XVIII), or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.

In another aspect, methods for co-regulating PI3K and mTOR are providedand include administering a therapeutically effective amount of acompound described herein to a patient in need thereof. Desirably,co-regulation includes inhibition of the PI3K/AKT/mTOR pathway.

In still a further aspect, methods for treating a disease characterizedby abnormal cellular growth resulting from a dysregulated PI3K/AKT/mTORpathway are provided. These methods include administering atherapeutically effective amount of a compound described herein to apatient in need thereof. In one embodiment, the disease is cancer. Inanother embodiment, the disease is characterized by the presence of atleast one solid tumor. In yet another embodiment, the disease ischaracterized by inflammation.

Other aspects and advantages of the invention will be readily apparentfrom the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds which have capabilitiesin modulating two (2) members of the PI3K/AKT/mTOR pathway, i.e., PI3Kand mTOR. These compounds are can be used to treat disease affected by adysregulation of the PI3K/AKT/mTOR pathway.

In the present invention, the compound is of formula (I), or apharmaceutically acceptable salt or solvate thereof.

In this structure, R¹ is H, F, Cl, or OCH₃.

R² is H, optionally substituted aryl, optionally substitutedheterocycle, optionally substituted heteroaryl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkylamino, optionally substituted dialkylamino,optionally substituted arylamino, optionally substitutedheteroarylamino, optionally substituted heterocycle-amino, optionallysubstituted alkylcarbonylamino, optionally substitutedalkylsulfonylamino, optionally substituted alkylthio, optionallysubstituted alkylsulfonyl, optionally substituted alkoxy, optionallysubstituted hydroxyalkyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycle-oxy,optionally substituted alkylaminocarbonyl, optionally substitutedarylaminocarbonyl, optionally substituted heteroarylaminocarbonyl,optionally substituted heterocycle-aminocarbonyl, or C(O)— (optionallysubstituted heterocycle) and R³ is H, halogen, CN, OH, NH₂, NHCH₃, orOCH₃. Alternatively, R² is H, halogen, CN, OH, NH₂, NHCH₃, or OCH₃ andR³ is H, optionally substituted aryl, optionally substitutedheterocycle, optionally substituted heteroaryl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkylamino, optionally substituted dialkylamino,optionally substituted arylamino, optionally substitutedheteroarylamino, optionally substituted heterocycle-amino, optionallysubstituted alkylcarbonylamino, optionally substitutedalkylsulfonylamino, optionally substituted alkylthio, optionallysubstituted alkylsulfonyl, optionally substituted alkoxy, optionallysubstituted hydroxyalkyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycle-oxy,optionally substituted alkylaminocarbonyl, optionally substitutedarylaminocarbonyl, optionally substituted heteroarylaminocarbonyl,optionally substituted heterocycle-aminocarbonyl, or C(O)— (optionallysubstituted heterocycle).

In one embodiment, R² or R³ is an optionally substituted phenyl group ofthe following structure. In this structure, n is 1 to 5 and each R¹⁰ isindependently selected from among OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, or cyanoalkyl. The phenyl ring may be attachedthrough any carbon atom of the ring and may be substituted with 1-5groups. In one example, the R² or R³ phenyl ring contains a substituentat the 3-position. In another example, the R² or R³ phenyl ring containsa substituent at the 4-position. In another example, the R² or R³ phenylring is substituted with OH, CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂,CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN,C(CH₃)₂CN, OCH₃, OCF₃, or SO₂CH₃.

In another embodiment, R² or R³ is optionally substituted heterocycle orheteroaryl. When the heterocycle or heteroaryl R² or R³ group containssubstituents, the same may be selected from among 1 to 3 R¹¹ groupsindependently selected from among OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, and cyanoalkyl.

In a further embodiment, R² or R³ is a heteroaryl of the followingformula, Z¹ is O, S, or NR¹²; Z² is CH or N; R¹² is absent, H or alkyl;p is 0 to 2; and each R¹¹ is, independently, selected from among OH,halogen, alkoxy, CF₃, OCF₃, CN, alkylamino, dialkylamino, hydroxyalkyl,alkylsulfonyl, alkylthio, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkylcarbonylamino, alkylsulfonylamino,alkylsulfonylalkyl, alkylaminocarbonyl, alkylaminosulfonyl, andcyanoalkyl. In another example, R² or R³ is selected from amongpyrazole, imidazole, pyrrole, thiophene and furan. In a further example,R² or R³ is selected from among pyrazole and imidazole. In still afurther example, the R² or R³ heteroaryl or heterocycle is substitutedwith CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂, CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂,CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN, C(CH₃)₂CN, OCH₃, OCF₃, orSO₂CH₃.

In still another embodiment, R² or R³ is a heteroaryl selected fromamong the following, m is 0 to 4, q is 0 to 3, each R¹⁴ is,independently, selected from among OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, and cyanoalkyl. In one example, R² or R³ is selectedfrom among pyridine, pyrimidine, and pyridazine. In another example, R²or R³ is substituted with CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂,CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN,C(CH₃)₂CN, OCH₃, OCF₃, or SO₂CH₃.

R⁴ in formula (I) is optionally substituted morpholine orthiomorpholine. In one embodiment, R⁴ is morpholine. In anotherembodiment, R⁴ is morpholine substituted by one or more methyl. In afurther embodiment, R⁴ is

R⁵ in formula (I) is H, F or Cl. R⁶ is H, F or Cl. In one embodiment, R⁵and R⁶ are both H.

X is N, CH, C—F or C—Cl. Y is N, CH, C—F or C—Cl. Z is N, CH, C—F, orC—Cl. A is CH or C—F.

M is selected from among

In one embodiment, M is

In another embodiment, M is

R⁷ and R⁸ as included in formula I are, independently, H or optionallysubstituted alkyl.

Alternatively, R⁷ and R⁸ are joined to form an optionally-substitutedheterocycle containing 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, 0 or 1sulfur atom, 0 or 1 S(O) fragment, 0 or 1 S(O)₂ fragment, and 3 to 6carbon atoms. In one embodiment, R⁷ and R⁸ are joined to form anoptionally substituted ring containing 1 nitrogen atom. In anotherembodiment, R⁷ and R⁸ are joined to form optionally substitutedpiperidinyl, pyrrolidinyl, azepanyl, piperazinyl, homopiperazinyl,morpholinyl, or thiomorpholinyl. In a further embodiment, R⁷ and R⁸ are,independently, H or alkyl optionally substituted with OH, halogen,alkoxy, CF₃, OCF₃, CN, alkylamino, dialkylamino, amino, alkylsulfonyl,alkylthio, alkylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl,or alkylaminosulfonyl. In yet another embodiment, R⁷ and R⁸ are,independently, H or alkyl optionally substituted with CH₂OH, CH₂CH₂OH,F, Cl, CN, NH₂, NH(CH₃), N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃, OCH₃,OCF₃, or SO₂CH₃. In still a further embodiment, R⁷ and R⁸ are joined toform a heterocycle optionally substituted with 0 to 3 groupsindependently selected from among OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, amino, hydroxyalkyl, alkylsulfonyl, alkylthio,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, and cyanoalkyl. In another embodiment, R⁷ and R⁸ arejoined to form a heterocycle substituted with 0 to 3 groupsindependently selected from among OH, CH₂OH, CH₂CH₂OH, F, Cl, CN, NH₂,NH(CH₃), N(CH₃)₂, CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃,CH₂CN, CH(CH₃)CN, C(CH₃)₂CN, OCH₃, OCF₃, and SO₂CH₃. In still a furtherembodiment, R⁷ and R⁸ are both CH₃.

R⁹ is H or alkyl and R¹⁰ is H or alkyl optionally substituted with OH,NH₂, NHCH₃, N(CH₃)₂, halogen, alkoxy, CF₃, OCF₃, or CN.

Alternatively, R⁹ and R¹⁰ are joined to form an optionally-substitutedheterocycle wherein the fragment —R⁹-R¹⁰— is optionally substituted—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, or —CH₂CH₂ CH₂ CH₂CH₂—.

In one embodiment, the compound is of formula (IA) or a pharmaceuticallysalt or solvate thereof, wherein R¹-R⁸, A, X, Y, and Z are defined above

In a further embodiment, the compound is of formula (IB) or apharmaceutically salt or solvate thereof, wherein R¹-R⁶, R⁹, R¹⁰, A, X,Y, and Z are defined above.

In yet a further embodiment, the compound is of formula (II) or apharmaceutically salt or solvate thereof, wherein R¹ is H or F.

In another embodiment, the compound is of formula (III) of apharmaceutically acceptable salt or solvate thereof, wherein R¹ is H orF.

In a further embodiment, the compound is of formula (IV), or apharmaceutically acceptable salt or solvate thereof.

In still another embodiment, the compound is of formula (V) or apharmaceutically acceptable salt or solvate thereof, wherein R¹ and R⁶are independently H or F.

In yet a further embodiment, the compound is of formula (V) or apharmaceutically acceptable salt or solvate thereof, wherein one of R⁵or R⁶ is F.

In another embodiment, the compound is of formula (VII) or apharmaceutically acceptable salt or solvate thereof, wherein R², R⁵, andM are defined herein.

In a further embodiment, the compound is of formula (VIII) or apharmaceutically acceptable salt or solvate thereof, wherein R², R⁵, andM are defined herein.

In yet another embodiment, the compound is of formula (b) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶ and Mare defined herein.

In still a further embodiment, the compound is of formula (X) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶, A,and M are defined herein.

In yet another embodiment, the compound is of formula (XI) or apharmaceutically acceptable salt or solvate thereof, wherein R² and R⁵are defined herein.

In a further embodiment, the compound is of formula (XII) or apharmaceutically acceptable salt or solvate thereof, wherein R² and R⁵are defined herein.

In still another embodiment, the compound is of formula (XIII) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶ and Aare defined herein.

In a further embodiment, the compound is of formula (XIV) or apharmaceutically acceptable salt or solvate thereof, wherein R² and R⁵are defined herein.

In yet another embodiment, the compound is of formula (XIV) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶ and Aare defined herein.

In still a further embodiment, the compound is of formula (XVI) or apharmaceutically acceptable salt or solvate thereof, wherein R² and R⁵are defined herein.

In another embodiment, the compound is of formula (XVII) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶ and Aare defined herein.

In a further embodiment, the compound is of formula (XVIII) or apharmaceutically acceptable salt or solvate thereof, wherein R¹-R⁶ and Aare defined herein.

Representative “pharmaceutically acceptable salts” include but are notlimited to water-soluble and water-insoluble salts. In one embodiment,the salt is of a base. In another embodiment, the salt is of an acid.The salt can be of an acid selected from, e.g., among acetic, propionic,lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, trifluoroacetic, and camphorsulfonic. Optionally, acomposition of the invention may contain both a pharmaceuticallyacceptable salt and the free base form of a compound of the invention.

In a further embodiment, a compound of the invention may be a solvate.As used herein, a solvate does not significantly alter the physiologicalactivity or toxicity of the compounds, and as such may function aspharmacological equivalents to non-solvate compounds of the invention.The term “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instances,the solvate can be isolated, such as when one or more solvent moleculesare incorporated into the crystal lattice of a crystalline solid. Thus,“solvate” encompasses both solution-phase and isolatable solvates.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each possible combination of chiral centers within acompound, as well as all possible enantiomeric mixtures thereof. Allchiral, diastereomeric, and racemic forms of a structure are intended,unless the specific stereochemistry or isomeric form is specificallyindicated. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials.

The following definitions are used in connection with the compoundsdescribed herein. In general, the number of carbon atoms present in agiven group is designated “C_(x) to C_(y)”, where x and y are the lowerand upper limits, respectively. The carbon number as used in thedefinitions herein refers to carbon backbone and carbon branching, butdoes not include carbon atoms of the substituents, such as alkoxysubstitutions and the like. Unless indicated otherwise, the nomenclatureof substituents that are not explicitly defined herein are determined bynaming from left to right the terminal portion of the functionalityfollowed by the adjacent functionality toward the point of attachment.As used herein, “optionally substituted” means that at least 1 hydrogenatom of the optionally substituted group has been replaced.

“Alkyl” refers to a hydrocarbon chain that may be straight or branched,or to a hydrocarbon group that consists of or contains a cyclic alkylradical. In one embodiment, an alkyl contains 1 to 8 (inclusive) carbonatoms or integers or ranges there between (2, 3, 4, 5, 6, or 7). Inanother embodiment, an alkyl contains 1 to 7 (inclusive) carbon atoms orranges there between. In a further embodiment, an alkyl contains 1 to 6(inclusive) carbon atoms. In yet another embodiment, an alkyl contains 1to 5 (inclusive) carbon atoms. In still a further embodiment, an alkylcontains 1 to 4 (inclusive) carbon atoms. Examples of alkyl groups thatare hydrocarbon chains include, but are not limited to, methyl, ethyl,propyl, butyl, pentyl, hexyl, and heptyl, where all isomers of theseexamples are contemplated. Examples of alkyl groups that consist of orcontain a cyclic alkyl radical include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, 3,3-dimethylcyclobutyl,(cyclopropyl)methyl, and (cyclopentyl)methyl. An alkyl can beunsubstituted or substituted with one or more groups including, withoutlimitation, halogen, OH, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl),NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆ alkyl),C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), CN, C₁ to C₆ alkoxy, C(O)OH,C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl, heteroaryl, NH(C₁ toC₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), OC(O)(C₁ to C₆ alkyl),optionally substituted heterocycle, and NO₂. In one embodiment, thesubstituted alkyl is CH₂OH.

“Alkenyl” refers to hydrocarbon chain which is straight or branched andcontains at least one degree of unsaturation (i.e., with one or morecarbon-carbon double bonds), or to a hydrocarbon group that consists ofor contains a cyclic alkenyl radical. Each alkenyl double bond may existin the E or Z conformation. In one embodiment, an alkenyl contains 2 toabout 8 (inclusive) carbon atoms or integers or ranges there between (3,4, 5, 6, or 7). In another embodiment, an alkenyl contains 2 to 7(inclusive) carbon atoms. In a further embodiment, an alkenyl contains 2to 6 (inclusive) carbon atoms. In yet another embodiment, an alkenylcontains 2 to 5 (inclusive) carbon atoms. In still a further embodiment,an alkenyl contains 2 to 4 (inclusive) carbon atoms. An alkenyl containsat least 1 double bond. In one embodiment, the alkenyl may contain 1, 2,3, or 4 double bonds. Examples of alkenyl hydrocarbon chain include, butare not limited to, ethene, propene, butene, pentene, hexene, heptene,and octene. Examples of alkenyl that consist of or contain a cyclicalkenyl radical include, but are not limited to, cyclopentene, andcyclohexene. An alkenyl can be unsubstituted or substituted with one ormore groups including, without limitation, halogen, OH, NH₂, N(C₁ to C₃alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂,C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), CN, C₁ toC₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl,heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),OC(O)(C₁ to C₆ alkyl), and NO₂.

“Alkynyl” refers to a hydrocarbon chain which is straight or branchedchain and contains at least one degree of unsaturation, i.e., with oneor more carbon-carbon triple bond. In one embodiment, an alkynylcontains 2 to about 8 (inclusive) carbon atoms or integers or rangesthere between (3, 4, 5, 6, or 7). In another embodiment, an alkynylcontains 2 to 7 (inclusive) carbon atoms. In a further embodiment, analkynyl contains 2 to 6 (inclusive) carbon atoms. In yet anotherembodiment, an alkynyl contains 2 to 5 (inclusive) carbon atoms. Instill a further embodiment, an alkynyl contains 2 to 4 (inclusive)carbon atoms. An alkynyl contains at least 1 triple bond. In oneembodiment, the alkynyl may contain 1, 2, 3, or 4 triple bonds. Examplesof alkynyl include, but are not limited to, ethyne, propyne, butyne,pentyne, hexyne, heptyne, and octyne. An alkynyl can be unsubstituted orsubstituted with one or more groups including, without limitation,halogen, OH, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ to C₆alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆alkyl)(C₁ to C₆ alkyl), CN, C₁ to C₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆alkyl), C(O)(C₁ to C₆ alkyl), aryl, heteroaryl, NH(C₁ to C₆ alkyl), N(C₁to C₆ alkyl)(C₁ to C₆ alkyl), OC(O)(C₁ to C₆ alkyl), and NO₂.

“Alkoxy” refers to (alkyl)O, where the alkyl is optionally substitutedand is defined above. In one embodiment, an alkoxy contains 1 to 8(inclusive) carbon atoms or integers or ranges there between (2, 3, 4,5, 6, or 7). In another embodiment, an alkoxy contains 1 to 7(inclusive) carbon atoms or ranges there between. In a furtherembodiment, an alkoxy contains 1 to 6 (inclusive) carbon atoms. In yetanother embodiment, an alkoxy contains 1 to 5 (inclusive) carbon atoms.In still a further embodiment, an alkoxy contains 1 to 4 (inclusive)carbon atoms. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, and butoxy. The alkyl radical of an alkoxygroup can be unsubstituted or substituted as defined above for “alkyl”.

“Hydroxyalkyl” refers to (alkyl)OH, where the alkyl is optionallysubstituted and is defined above. The OH moiety of the hydroxyalkyl maybe bound to any carbon atom, for example, any one of the internal carbonatoms or the terminal carbon atom of a hydrocarbon alkyl chain. In oneembodiment, a hydroxyalkyl contains 1 to 8 (inclusive) carbon atoms orintegers or ranges there between (2, 3, 4, 5, 6, or 7). In anotherembodiment, a hydroxyalkyl contains 1 to 7 (inclusive) carbon atoms orranges there between. In a further embodiment, a hydroxyalkyl contains 1to 6 (inclusive) carbon atoms. In yet another embodiment, a hydroxyalkylcontains 1 to 5 (inclusive) carbon atoms. In still a further embodiment,a hydroxyalkyl contains 1 to 4 (inclusive) carbon atoms. Examples of ahydroxyalkyl include, but are not limited to, CH₂OH, CH₂CH₂OH,CH(OH)CH₃, CH₂CH₂CH₂OH, CH₂CH(OH)CH₃, CH(OH)CH₂CH₃, C(OH)(CH₃)₂,(2-hydroxy)-cyclopentyl, (3-hydroxy)-cyclobutyl, and the like.

“Cyanoalkyl” refers to (alkyl)CN, where the alkyl is optionallysubstituted and is defined above. The CN moiety of the cyanoalkyl may bebound to any carbon atom; for example, any one of the internal carbonatoms or the terminal carbon atom of a hydrocarbon alkyl chain. In oneembodiment, a cyanoalkyl contains 1 to 8 (inclusive) carbon atoms orintegers or ranges there between (2, 3, 4, 5, 6, or 7). In anotherembodiment, a cyanoalkyl contains 1 to 7 (inclusive) carbon atoms orranges there between. In a further embodiment, a cyanoalkyl contains 1to 6 (inclusive) carbon atoms. In yet another embodiment, a cyanoalkylcontains 1 to 5 (inclusive) carbon atoms. In still a further embodiment,a cyanoalkyl contains 1 to 4 (inclusive) carbon atoms. Examples ofcyanoalkyl include, but are not limited to, CH₂CN, CH₂CH₂CN, CH(CN)CH₃,CH₂CH₂CH₂CN, CH₂CH(CN)CH₃, CH(CN)CH₂CH₃, C(CN)(CH₃)₂,(2-cyano)-cyclopentyl, (3-cyano)-cyclobutyl, and the like.

“Aryl” refers to an aromatic hydrocarbon group containing carbon atoms.In one embodiment, the aryl contains 6, 7 or 8 carbon atoms, and isphenyl or is an aromatic or partly aromatic bicyclic group. In a furtherembodiment, the aryl is a phenyl group. In another embodiment, the arylis naphthyl (such as α-naphthyl or (β-naphthyl),1,2,3,4-tetrahydronaphthyl, or indanyl. An aryl group can beunsubstituted or substituted with one or more groups including, withoutlimitation, halogen, OH, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl),NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆ alkyl),C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), C₁ to C₆ alkyl, CN, C₁ to C₆alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl,heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),OC(O)(C₁ to C₆ alkyl), and NO₂. In one embodiment, an aryl issubstituted with one or more halogen, OH, CN, NH₂, C₁ to C₆ alkylamino,C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, C₁ to C₆ haloalkyl,OCF₃, SO₂(C₁ to C₆ alkyl), or NHSO₂(C₁ to C₆ alkyl). In anotherembodiment, an aryl is substituted with one halogen, OH, CN, NH₂, C₁ toC₆ alkylamino, C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, CF₃,OCF₃, SO₂CH₃, NHCOCH₃, or NHSO₂CH₃. In a further embodiment, an aryl issubstituted with one halogen, OH, CN, N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃,SO₂CH₃, NHCOCH₃, or NHSO₂CH₃.

“Halogen” refers to F, Cl, Br and I.

The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

“Heteroaryl” refers to a monocyclic aromatic 5- or 6-membered ringcontaining at least one ring heteroatom. In one embodiment, theheteroaryl contains 1 to 5 carbon atoms (inclusive) or integers orranges there between (2, 3, or 4). In a further embodiment, theheteroaryl contains 2 to 5 carbon atoms (inclusive). In anotherembodiment, the heteroaryl contains 3 to 5 carbon atoms (inclusive). Instill a further embodiment, the heteroaryl contains 4 or 5 carbon atoms.“Heteroaryl” also refers to bicyclic aromatic ring systems wherein aheteroaryl group as just described is fused to at least one other cyclicmoiety. In one embodiment, a phenyl radical is fused to a 5- or6-membered monocyclic heteroaryl to form the bicyclic heteroaryl. Inanother embodiment, a cyclic alkyl is fused to a monocyclic heteroarylto form the bicyclic heteroaryl. In yet a further embodiment, thebicyclic heteroaryl is a pyridine fused to a 5- or 6-membered monocyclicheteroaryl. In another embodiment, the bicyclic heteroaryl is apyrimidine fused to a 5- or 6-membered monocyclic heteroaryl. In yet afurther embodiment, the bicyclic heteroaryl is a pyridazine fused to a5- or 6-membered monocyclic heteroaryl. In still another embodiment, theheteroaryl ring has 1 or 2 nitrogen atoms in the ring. In a furtherembodiment, the heteroaryl ring has 1 nitrogen atom and 1 oxygen atom.In yet another embodiment, the heteroaryl ring has 1 nitrogen atom and 1sulfur atom. Examples of heteroaryl groups include, without limitation,furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole,isothiazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine,pyrrole, pyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole,benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole,azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Aheteroaryl may be unsubstituted or substituted with one or more groupsincluding, without limitation, halogen, C₁ to C₆ alkyl, OH, C₁ to C₆hydroxyalkyl, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ toC₆ alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆alkyl)(C₁ to C₆ alkyl), CN, C₁ to C₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆alkyl), C(O)(C₁ to C₆ alkyl), aryl, heteroaryl, NH(C₁ to C₆ alkyl), N(C₁to C₆ alkyl)(C₁ to C₆ alkyl), OC(O)(C₁ to C₆ alkyl), NH(C₁ to C₆hydroxyalkyl), N(C₁ to C₆ hydroxyalkyl)₂, C(O)NH[—(C₁ to C₆ alkyl)-N(C₁to C₆ alkyl)₂], C(O)NH[—(C₁ to C₆ alkyl)-NH(C₁ to C₆ alkyl)], C(O)N(C₁to C₆ alkyl)[—(C₁ to C₆ alkyl)-N(C₁ to C₆ alkyl)₂] and NO₂. In oneembodiment, a heteroaryl is substituted with one or more halogen, OH,CN, NH₂, C₁ to C₆ alkylamino, C₁ to C₆ alkyl substituted with OH, C₁ toC₆ alkoxy, C₁ to C₆ haloalkyl, OCF₃, SO₂(C₁ to C₆ alkyl), NHCOCH₃, orNHSO₂(C₁ to C₆ alkyl). In another embodiment, a heteroaryl issubstituted with one halogen, OH, CN, N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃,SO₂CH₃, NHCOCH₃, or NHSO₂CH₃.

“Heterocycle” refers to a monocyclic or bicyclic group in which at least1 ring atom is a heteroatom. A heterocycle may be saturated or partiallysaturated. In one embodiment, the heterocycle contains 3 to 7 carbonatoms (inclusive) or integers or ranges there between (4, 5, or 6). In afurther embodiment, the heterocycle contains 4 to 7 carbon atoms(inclusive). In another embodiment, the heterocycle contains 4 to 6carbon atoms (inclusive). In still a further embodiment, the heterocyclecontains 5 or 6 carbon atoms (inclusive). Examples of heterocyclesinclude, but are not limited, to aziridine, oxirane, thiirane,morpholine, thiomorpholine, pyrroline, pyrrolidine, azepane,dihydrofuran, THF, dihydrothiophene, tetrahydrothiophene, dithiolane,piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran,thiane, thiine, piperazine, homopiperazine, oxazine, azecane,tetrahydroquinoline, perhydroisoquinoline,5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane,2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane,3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane,7-oxa-2,5-diazabicyclo[2.2.2]octane,2,7-dioxa-5-azabicyclo[2.2.2]octane,2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane,3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane,3-oxa-8-azabicyclo[3.2.1]octan-8-yl,5,7-dioxa-2-azabicyclo[2.2.2]octane,6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,8-oxa-3-azabicyclo[3.2.1]octan-3-yl,2,5-diazabicyclo[2.2.1]heptane-5-yl, 6-azabicyclo[3.2.1]oct-6-yl,8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. Inanother embodiment, the heterocycle contains 1 or 2 nitrogen atoms. In afurther embodiment, the heterocycle contains 1 or 2 nitrogen atoms and 3to 6 carbon atoms. In yet another embodiment, the heterocycle contains 1or 2 nitrogen atoms, 3 to 6 carbon atoms, and 1 oxygen atom. In still afurther embodiment, the heterocycle is morpholine. In one embodiment,the heterocycle is morpholine and is substituted with one or more C₁ toC₃ alkyl. In another embodiment, the heterocycle is morpholine and 2carbons of the heterocycle are joined to form a 4- or 5-membered ring. Aheterocycle may be unsubstituted or substituted with one or more groupsincluding, without limitation, halogen, C₁ to C₆ alkyl, OH, NH₂, N(C₁ toC₃ alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂,C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), CN, C₁ toC₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl,heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),OC(O)(C₁ to C₆ alkyl), NH(C₁ to C₆ hydroxyalkyl), N(C₁ to C₆hydroxyalkyl)₂, C(O)NH[—(C₁ to C₆ alkyl)-N(C₁ to C₆ alkyl)₂],C(O)NH[—(C₁ to C₆ alkyl)-NH(C₁ to C₆ alkyl)], C(O)N(C₁ to C₆ alkyl)[—(C₁to C₆ alkyl)-N(C₁ to C₆ alkyl)₂] and NO₂. In one embodiment, aheterocycle is substituted with one or more halogen, OH, CN, NH₂, C₁ toC₆ alkylamino, C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, C₁to C₆ haloalkyl, OCF₃, SO₂(C₁ to C₆ alkyl), NHCOCH₃, or NHSO₂(C₁ to C₆alkyl). In another embodiment, a heterocycle is substituted with one F,OH, CN, NH₂, N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃, SO₂CH₃, NHCOCH₃, orNHSO₂CH₃.

“Optionally-substituted —CH₂CH₂CH₂—, —CH₂CH₂ CH₂CH₂—, or—CH₂CH₂CH₂CH₂CH₂—” refers to —CH₂CH₂CH₂—, —CH₂CH₂ CH₂CH₂—, or —CH₂CH₂CH₂ CH₂CH₂— wherein 1 or 2 of the hydrogen atoms are replaced with OH,NH₂, NHCH₃, N(CH₃)₂, halogen, alkoxy, CF₃, OCF₃, or CN.

“C₁ to C₆ haloalkyl” refers to a C₁ to C₆ alkyl group, as defined above,wherein one or more of the C₁ to C₆ alkyl group's hydrogen atoms hasbeen replaced with F, Cl, Br, or I. Each substitution can beindependently selected from F, Cl, Br, or I. Representative examples ofan C₁ to C₆ haloalkyl group include, but are not limited to, CH₂F, CF₃,CH₂CF₃, and the like.

“Alkylthio” refers to (alkyl)S

, where the alkyl is optionally substituted and is defined above. In oneembodiment, an alkylthio contains 1 to 8 (inclusive) carbon atoms orintegers or ranges there between (2, 3, 4, 5, 6, or 7). Examples ofalkylthio include, but are not limited to, SCH₃, SCH₂CH₃, SCH₂CH₂CH₃,and SCH₂CH₂CH₂CH₃.

“Aryloxy” refers to (aryl)O

, where the aryl is defined above and is optionally substituted asdescribed above. An aryloxy group is attached through the oxygen atommoiety. Examples of aryloxy include, but are not limited to, phenoxy andpentafluorophenoxy.

“Heteroaryloxy” refers to (heteroaryl)O

, where the heteroaryl is optionally substituted and is defined above.The heteroaryloxy moiety is bound through the oxygen atom moiety.Examples of heteroaryloxy include, but are not limited to,(3-pyridyl)oxy and (4-pyridyl)oxy.

“Heterocycle-oxy” refers to (heterocycle)O

, where the heterocycle is optionally substituted and is defined above.The heterocycle-oxy moiety is bound through the oxygen atom. Examples ofheterocycleoxy include, but are not limited to, (4-piperidinyl)oxy.

“Alkylsulfonyl” refers to an (alkyl)SO₂

group, which is bound through the SO₂ moiety. The alkyl group is definedand optionally substituted as described above. Examples of alkylsulfonylinclude, but are not limited to, CH₃SO₂, CH₃CH₂CH₂SO₂, CH₃CH(CH₃)SO₂,CH₃CH₂CH₂CH₂SO₂, CH₃CH(CH₃)CH₂SO₂, (CH₃)₃CSO₂, and the like.

“Alkylsulfonylalkyl” refers to an (alkyl)SO₂(alkyl) group, which isbound through one of the alkyl groups. The alkyl group is defined andoptionally substituted as described above. The alkyl groups may be thesame or different. Examples of alkylsulfonylalkyl include, but are notlimited to, 3-(methylsulfonyl)propyl and 3-(methylsulfonyl)cyclopentyl.

“Alkylamino” refers to an NH or N group, the nitrogen atom of said groupbeing attached to 1 or 2 alkyl substituents, respectively, where alkylis as defined above. The alkylamino is bound through the nitrogen atomof the group. In one embodiment, alkylamino refers to a (alkyl)NH

group. In another embodiment, alkylamino refers to a (alkyl)(alkyl)N

group, i.e., a “dialkylamino”. When the nitrogen atom is bound to 2alkyls, each alkyl group may be independently selected. In anotherembodiment, two alkyl groups on the nitrogen atom may be taken togetherwith the nitrogen to which they are attached to form a 3- to 7-memberednitrogen-containing heterocycle wherein up to two of the carbon atoms ofthe heterocycle can be replaced with N(H), N(C₁ to C₆ alkyl), N(aryl),N(heteroaryl), O, S, S(O), or S(O)₂. Examples of alkylamino include, butare not limited to CH₃NH, CH₃CH₂NH, CH₃CH₂CH₂NH, CH₃CH₂CH₂CH₂NH,(CH₃)₂CHNH, (CH₃)₂CHCH₂NH, CH₃CH₂CH(CH₃)NH, (CH₃)₃CNH, N(CH₃)₂,N(CH₂CH₃)(CH₃), N(CH₂CH₃)₂, N(CH₂CH₂CH₃)₂, N(CH₂CH₂CH₂CH₃)₂,N(CH(CH₃)₂)(CH₃), and the like.

“Aminoalkyl” refers to an alkyl group having an NH₂ substituent. Theaminoalkyl is bound through one carbon atom of the group. That is,alkylamino refers to a NH₂(alkyl)

group. Examples of aminoalkyl include, but are not limited to CH₂NH₂,CH₂CH₂NH₂, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂CH₂NH₂, C(CH₃)₂NH₂, C(CH₃)₂CH₂NH₂, andthe like.

“Alkylaminoalkyl” refers to an (alkyl)NH(alkyl)

group, the nitrogen atom of being attached to 2 alkyl substituents,respectively, as defined above, and where the group is bound through oneof the alkyl groups. Each of the alkyl groups may be independentlyselected and substituted as described above. In another embodiment, thealkyl groups may be taken together with the nitrogen to which they areattached to form a 3- to 7-membered nitrogen containing heterocyclewherein up to two of the carbon atoms of the heterocycle can be replacedwith N(H), N(C₁ to C₆ alkyl), N(aryl), N(heteroaryl), O, S, S(O), orS(O)₂. Examples of alkylaminoalkyl include, but are not limited toCH₃NHCH₂, CH₃NHCH₂CH₂, CH₃NHCH(CH₃), CH₃CH₂NHCH₂, CH₃CH₂NHCH₂CH₂,CH₃CH₂NHCH(CH₃), and the like.

“Dialkylaminoalkyl” refers to an (alkyl)₂N(alkyl)

group, the nitrogen atom of being attached to 3 alkyl substituents,respectively, as defined above, and where the group is bound through oneof the alkyl groups. Each of the alkyl groups may be independentlyselected and substituted as described above. In another embodiment, twoof the alkyl groups may be taken together with the nitrogen to whichthey are attached to form a 3- to 7-membered nitrogen containingheterocycle wherein up to two of the carbon atoms of the heterocycle canbe replaced with N(H), N(C₁ to C₆ alkyl), N(aryl), N(heteroaryl), O, S,S(O), or S(O)₂. Examples of dialkylaminoalkyl include, but are notlimited to (CH₃)₂NCH₂, (CH₃)₂NCH₂CH₂, (CH₃)₂NCH(CH₃), (CH₃CH₂)₂NCH₂,(CH₃CH₂)₂NCH₂CH₂, (CH₃CH₂)₂NCH(CH₃), (CH₃)(CH₃CH₂)NCH₂, and the like.

“Arylamino” refers to an (aryl)NH

group, where aryl is optionally substituted and defined as above. Thearylamino is bound through the nitrogen atom. Examples of arylaminoinclude, but are not limited to, phenyl-amino.

“Heteroarylamino” refers to a (heteroaryl)NH

group, where heteroaryl is optionally substituted and defined as above.The heteroarylamino is bound through the amino nitrogen atom. Examplesof heteroarylamino include, but are not limited to (pyridin-2-yl)aminoand (pyrimidin-2-yl)amino.

“Heterocycle-amino” refers to a (heterocycle)NH

group, where heterocycle is optionally substituted and defined as above.Examples of heterocycle-amino include, but are not limited to(piperidin-4-yl)amino.

“Alkylcarbonylamino” refers to an (alkyl)C(O)NH

group, which is bound through the nitrogen atom. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylcarbonylamino include, but are not limited to, CH₃CONH, CH₃CH₂CONH,CH₃CH₂CH₂CONH, CH₃CH(CH₃)CONH, and the like.

“Alkylsulfonylamino” refers to an (alkyl)SO₂NH

group which is bound through the nitrogen atom. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylsulfonylamino include, but are not limited to CH₃SO₂NH,CH₃CH₂SO₂NH, CH₃CH₂CH₂SO₂NH, CH₃CH(CH₃)SO₂NH, and the like.

“Alkylaminocarbonyl” refers to an (alkyl)NHC(O)

group, which is bound through the carbonyl moiety. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylaminocarbonyl include, but are not limited to, CH₃NHCO, CH₃CH₂NHCO,CH₃CH₂CH₂NHCO, CH₃CH(CH₃)NHCO, and the like.

“Alkylaminosulfonyl” refers to an (alkyl)NHSO₂

group, which is bound through the sulfur atom. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylaminosulfonyl include, but are not limited to, CH₃NHSO₂,CH₃CH₂NHSO₂, CH₃CH₂CH₂NHSO₂, CH₃CH(CH₃)NHSO₂, and the like.

“Arylaminocarbonyl” refers to an (aryl)NHC(O)

group, which is bound through the carbon atom of the carbonyl moiety.The aryl group is defined and optionally substituted as described above.Examples of arylaminocarbonyl include, but are not limited tophenyl-NHC(O)—.

“Heteroarylaminocarbonyl” refers to an (heteroaryl)NHC(O)

group, which is bound through the carbon atom of the carbonyl moiety.The heteroaryl group is defined and optionally substituted as describedabove. Examples of heteroarylaminocarbonyl include, but are not limitedto (pyridine-4-yl)NHC(O).

“Heterocycleaminocarbonyl” refers to an (heterocycle)NHC(O)

group, which is bound through the carbonyl moiety. The heterocycle groupis defined and optionally substituted as described above. Examples ofheterocycleaminocarbonyl include, but are not limited to(tetrahydro-2H-pyran-4-yl)NHC(O).

A “patient” or “subject” is a mammal, e.g., a human or a veterinarypatient or subject, e.g., mouse, rat, guinea pig, dog, cat, horse, cow,pig, or non-human primate, such as a monkey, chimpanzee, baboon orgorilla.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration of one or more symptoms of a disease or disorder, includingpalliative care. A “therapeutically effective amount” refers to theminimum amount of the active compound which effects treatment.

The following abbreviations are used herein and have the indicateddefinitions: ACN is acetonitrile; BCA is bicinchoninic acid; bid pomeans twice daily by mouth; conc is concentrated; DMSO isdimethylsulfoxide; DCC is dicyclohexylcarbodiimide; DCM isdichloromethane; DIPEA is diisopropylethylamine; DMF isN,N-dimethylformamide; dppf is 1,1′-bis(diphenylphosphino)ferrocene; DTTis dithiothreitol; EDCI.HCl is1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EDTA isethylenediamine tetraacetic acid; EGTA is ethylene glycol tetraaceticacid; ELISA is enzyme-linked immunosorbent assay; EtOH is ethanol; ESIis electrospray ionization; EI is electron impact ionization; HATU is2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium; HEPES is(4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid; HPCD ishydroxypropyl-β-cyclodextrin; HPLC is high performance liquidchromatography; Hz is hertz; HOAt is 1-hydroxy-7-azabenzotriazole; HOBtis 1-hydroxy benzotriazole; KOAc is potassium acetate; LC is liquidchromatography; MS is mass spectroscopy; MeOH is MeOH; MHz is megahertz;mM is millimolar; mL is milliliter; min is minutes; mol is moles; M⁺ ismolecular ion; [M+H]⁺ is protonated molecular ion; N is normality; NMRis nuclear magnetic resonance; PIP2 is 5-bisphosphate; PBS is phosphatebuffered saline; PH is pleckstrin homology; PMSF isphenylmethanesulfonyl fluoride; PPh₃ is triphenylphosphine; psi is poundper square inch; PPM is parts per million; qd po means daily by mouth;rt is room temperature; RT is retention time; TLC is thin layerchromatography; TFA is trifluoroacetic acid; TEA is triethylamine; THFis tetrahydrofuran; TMS is tetramethylsilane; and XTT is sodium2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazoliuminner salt.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein, the term “about” means a variability of 10% from thereference given, unless otherwise specified.

Methods useful for making the compounds of formula (I) are set forth inthe Examples below and generalized in Schemes 1-15. One of skill in theart will recognize that Schemes 1-15 can be adapted to produce the othercompounds of formula (I) and pharmaceutically acceptable salts ofcompounds of formula (I) according to the present invention.

The following methods outline the synthesis of the compounds of formula(I). The following examples are presented to illustrate certainembodiments of the present invention, but should not be construed aslimiting the scope of this invention.

Scheme 1 depicts a first synthesis of the boronic acid pinacol esterintermediate compound [1]. Specifically, a 4-nitrobenzoic acid [A] isconverted to the corresponding amide [B] using an amine such as R⁷R⁸NH,a coupling agent such as EDCI.HCl, DCC, HBTU, or HATU, an additive suchas HOBt or HOAt, a base such as TEA or DIPEA and solvent such as DMF,THF, or DCM. In one embodiment, the amine may be NH₃, NH₂CH₃, NH(CH₃)₂,morpholine, piperidine, 1-methyl-piperazine and N(CH₃)₂CH₂CH₂N(CH₃)₂,among others. Typically, this is performed at rt such as about 25 toabout 30° C. for about 10 to about 15 h such as about 10 h. The 4-nitroamide [B] is then reduced to the corresponding amine [C] using H₂ and acatalyst such as Pd/C 10%, PtO₂, or Pd(OH)₂. Typically, the reduction isperformed under pressures such as 60 psi, in a solvent such as MeOH,dioxane, or ethylacetate, for about 3 to about 5 h such as about 3 h.Amine [C] is then converted to urea [D] using an appropriatelysubstituted isocyanate such as 4-bromophenyl isocyanate. This reactionis typically performed in the presence of a base such as TEA or DIPEAand solvent such as CH₂Cl₂, CHCl₃, or THF at about rt such as about 25to about 30° C. for about 5 to about 15 h such as about 12 h. As onealternative method, amine [α] can be converted to the corresponding2,2,2-trichloro-ethyl carbamate and then reacted with an appropriatelysubstituted aniline or pyridinyl amine, to produce the desired urea [D].For example, amine [C] would typically be treated with2,2,2-trichloroethyl chloroformate in the presence of a base such astriethylamine or DIPEA, in a solvent such as CH₂Cl₂, CHCl₃, or THF, attemperatures such as 0° C. to about 30° C. for about 30 minutes to 5hours, to produce the 2,2,2-tri-chloroethyl carbamate intermediate. Thenthe 2,2,2-trichloroethyl carbamate intermediate is typically reactedwith the aniline or pyridinyl amine in the presence of a base such astriethylamine or DIPEA, in a solvent such as toluene, 1,4-dioxane orTHF, at about room temperature up to elevated temperatures such as about110° C. for about 1 to 16 hours. This alternative two-step procedureprovides the urea [D]. Intermediate boronic acid pinacal ester [1] isthen formed by reacting urea [D] with bis(pinacolato)diboron. Thisreaction may be performed in the presence of a weak base such as KOAc,palladium catalyst such as Pd(dppf)Cl₂.DCM or Pd(dppf)Cl₂, in a solventsuch as 1,4-dioxane or DMF. Desirably, the reaction is performed atelevated temperatures such as the reflux temperatures of the solvent. Inone embodiment, this reaction is performed at about 80 to about 120° C.for about 2 to about 15 h. In another embodiment, this reaction isperformed at about 110° C. for about 10 h.

Scheme 1A depicts the synthesis of the boronic acid intermediatecompound [1A]. In one embodiment, 4-nitrobenzoic acid [A1] is convertedto the corresponding amide [B1] using R⁷R⁸NH and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl),HOBt and TEA in DMF at rt for about 10 h. The 4-nitro amide [B1] is thenreduced to the corresponding amine [C1] using H₂ and Pd/C 10% at 60 psi,in MeOH for about 3 h. Amine [C1] is then converted to urea [D1] using4-bromophenyl isocyanate in the presence of TEA in CH₂Cl₂ at about rtfor about 12 h. Intermediate boronic acid pinacol ester [1A] is thenformed by reacting urea [D1] with bis(pinacolato)diboron in the presenceof KOAc, Pd(dppf)Cl₂.DCM, 1,4-dioxane at 110° C. for about 10 h.

Scheme 2 provides a second synthesis of the boronic acid pinacol esterintermediate [1]. Intermediate compound [C] is prepared as described inScheme 1. In a separate reaction, an appropriately substituted anilinesuch as 4-bromo aniline [H] is converted to the corresponding carbamate[J] using 2,2,2-trichloroethyl chloroformate or trichloromethylchloroformate and a base such as TEA or DIPEA. Typically, thisconversion is performed in the presence of a solvent such as DCM, CHCl₃,or THF at reduced temperatures, i.e., about 0° C. to rt, for about 2 toabout 4 hours, for example about 4 h. It will be recognized by thoseskilled in the art that in certain cases, when the desired aniline [H]is not commercially available, it can be prepared by methods known inthe art. For example, 4-bromo-2,3-difluoroaniline is prepared byreaction of 2,3-difluoroaniline with tetrabutylammonium tribromide, asdescribed in Int. Pat. Appl. WO2010091272 (2010). An amine such asintermediate compound [C] is then coupled with carbamate [J] in thepresence of a base such as TEA or DIPEA and in a solvent such as1,4-dioxane, toluene, or mixtures thereof to form urea [K]. Typically,the coupling is performed at elevated temperatures, i.e., about 90 toabout 110° C. such as about 95° C., for about 10 to about 15 h, such asabout 10 h. Reaction of urea [K] with bis(pinacolato)diboron in thepresence of a catalyst such as Pd(dppf)Cl₂ DCM or Pd(dppf)Cl₂ providesintermediate [1]. Typically, this reaction is performed in the presenceof a base such as KOAc, a solvent such as 1,4-dioxane or DMF, and atelevated temperatures such as about 80 to about 120° C., such as about110° C., for about 2 to about 15 h, such as about 10 h.

Scheme 2A provides a synthesis of boronic acid intermediate [1B].Intermediate compound [C1] is prepared as described in Scheme 1A. In aseparate reaction, 2-fluoro-4-bromo aniline [H] is converted to thecorresponding carbamate [J1] using 2,2,2-trichloroethyl chloroformateand TEA in the presence of DCM at about 0° C. to rt for about 4 h.Intermediate compound [C1] is then coupled with carbamate [J1] in thepresence of TEA and 1,4-dioxane at about 95° C., for about 10 h to formurea [K1]. Reaction of urea [K1] with bis(pinacolato)diboron in thepresence of Pd(dppf)Cl₂.DCM, KOAc, and 1,4-dioxane at 110° C. for about10 h provides intermediate [1B].

Scheme 3 provides a third route to intermediate [1]. In this route, anappropriately substituted aniline, such as 4-bromoaniline [H], isreacted with an appropriate isocyanate such as ethyl4-isocyanatobenzoate to form the corresponding urea [M]. Typically, thisreaction is performed in a solvent such as DCM or CHCl₃, base such asTEA or DIPEA, at about rt, such as about 25 to about 30° C., for about 3to about 6 h, such as about 3 h. The ester moiety of urea [M] is thenhydrolyzed to the corresponding benzoic acid [N] using a base such asLiOH.H₂O or NaOH in one or more solvents such as EtOH, THF, and/or waterover a period of about 6 to about 12 h, such as about 6 h. Conversion ofthe benzoic acid [N] to benzamide [O] is performed using an amine suchas R⁷R⁸NH, with coupling agents such as EDCI.HCl, DCC, HATU, or HBTU,and HOBt or HOAt. Typically, benzamide [O] is prepared using a base suchas TEA or DIPEA, in solvent such as DMF, THF, or DCM, at rt, such asabout 25 to about 30° C., over a period of about 10 to about 15 h, suchas about 10 h. Conversion of benzamide [O] to intermediate [1] isperformed using the reagents and conditions described in step e ofScheme 2.

In one embodiment, Scheme 3A provides a third synthesis of intermediate[1B]. In this route, 2-fluoro-4-bromoaniline [H1] is reacted with ethyl4-isocyanatobenzoate in DCM and TEA at about rt for about 3 h to formthe corresponding urea [M1]. The ester moiety of urea [M] is thenhydrolyzed to the corresponding benzoic acid [N1] using LiOH.H₂O, inEtOH, THF, and water over a period of about 6 h. Conversion of thebenzoic acid [N1] to benzamide [01] is performed using R⁷R⁸NH, EDCI.HCland HOBt in the presence TEA and DMF at rt over a period of about 10 h.Conversion of benzamide [O1] to intermediate [1B] is performed using thereagents and conditions described in step e of Scheme 2A.

The fourth route to intermediate [1] is outlined in Scheme 4.Intermediate compound [C] is prepared as described in Scheme 2. 4-Aminobenzamide [C] is then reacted with 2,2,2-trichloroethyl chloroformate ortrichloromethyl chloroformate to form the corresponding carbamate [P].Typically, this reaction is performed in the presence of a base such asTEA or DIPEA, solvent such as DCM, THF, or CHCl₃, at reducedtemperatures, i.e., about 0° C. to about rt, for about 2 to about 12 h,such as about 4 h. Reaction of compound [P] with an appropriatelysubstituted aniline affords urea intermediate [O]. Typically, thisreaction is performed in the presence of a base such as TEA or DIPEA, asolvent such as 1,4-dioxane, toluene, or mixtures thereof, at elevatedtemperatures such as about 90 to about 120° C., i.e., about 95° C., andover a period of about 10 to about 15 h, such as about 10 h. The ureaintermediate [O] is then reacted with bis(pinacolato)diboron in thepresence of a catalyst such as Pd(dppf)Cl₂.DCM or Pd(dppf)Cl₂ to formintermediate [1]. Typically, this reaction is performed in the presenceof a base such as KOAc, solvent such as 1,4-dioxane or DMF, at elevatedtemperatures such as about 80 to about 120° C., such as about 110° C.,and over a period of about 3 to about 15 h, such as about 10 h.

In one embodiment, intermediate [1B] is prepared as described inoutlined in Scheme 4A. Intermediate compound [C1] is prepared asdescribed in Scheme 2A. 4-amino benzamide [C1] is then reacted with2,2,2-trichloroethyl chloroformate in TEA and DCM at about 0° C. toabout rt for about 4 h to form the corresponding carbamate [P1].Reaction of compound [P1] with 4-bromo-2-fluoroaniline in TEA and1,4-dioxane, at about 95° C. for about 10 h affords urea intermediate[O1]. The urea intermediate [O1] is then reacted withbis(pinacolato)diboron and Pd(dppf)Cl₂.DCM, KOAc and 1,4-dioxane atabout 110° C. for about 10 h to form intermediate [1B].

Scheme 5 provides an alternate synthesis of intermediate compound [1].In this route, benzoic acid [Q] is converted to corresponding amide [R]using an amine such as R⁷R⁸NH, coupling agents such as EDCI.HCl, DCC,HATU, or HBTU, and HOBt or HOAt, a base such as TEA or DIPEA, and DMF,DCM, or THF. The nitro amide [R] is then reduced using tin chemistry toprovide amino-substituted benzamide [S]. Benzamide [S] is then convertedto urea [T] using an appropriately substituted isocyanate in thepresence of a base and solvent. Conversion of urea [T] to intermediate[1] is accomplished using the same reagents and conditions as describedin step e of Scheme 4, i.e., Pd(dppf)Cl₂.DCM or Pd(dppf)Cl₂,bis(pinacolato)diboron, KOAc, and 1,4-dioxane or DMF at elevatedtemperatures of about 80 to about 120° C. over a period of about 3 toabout 15 h.

In one embodiment, intermediate [1C] is prepared according to Scheme 5A.In this route, 3-fluoro-4-nitro benzoic acid [Q1] is converted tocorresponding amide [R1] using R⁷R⁸NH, EDCI.HCl, HOBt, TEA, and DMF atabout rt for about 10 h. Amide [R1] is then reduced using SnCl₂ in EtOHat reflux for about 3-4 h to provide benzamide [S1]. Benzamide [S1] isthen converted to urea [T1] using 4-bromophenylisocyanate in thepresence of TEA and DCM at about rt. Conversion of urea [T1] tointermediate [1C] is accomplished using Pd(dppf)Cl₂.DCM,bis(pinacolato)diboron, KOAc, and 1,4-dioxane, at about 110° C. forabout 10 h.

Schemes 6-8 describe the preparation of compounds encompassed by genericformula (I).

Scheme 6 provides the synthesis of compounds which are encompassed bythe structure of formula (I) when X, Y, and Z are CH and R³ is H.Specifically, a 3-bromoaniline [U] is converted to the correspondinghydroxylamine [V] using chloral hydrate and NH₂OH.HCl. Reaction ofcompound [V] with a strong acid such as H₂SO₄ results in the preparationof cyclic isatin [W]. The isatin ring of [W] is then cleaved using H₂O₂.The resultant acid [α] is converted to quinazolinedione [Y] using urea.Quinazolinedione [Y] is then chlorinated at the 2- and 4-positions toform compound [Z] using chlorinating agents. The 4-position ofquinazoline [Z] is then substituted by reaction with an optionallysubstituted morpholine or thiomorpholine to afford compound [AA]. The7-position of quinazoline compound [AA] is then R²-substituted bycoupling with a reagent such as R²B(OR)₂, R²SnBu₃, R²MgCl, or R²ZnCl.Finally, intermediate [BB] is reacted with intermediate [1].

Scheme 6A provides the synthesis of compounds which are encompassed bythe structure of formula (I) when X, Y, and Z are CH and R² is H.Specifically, a 2-bromoaniline [Ua] is converted to the correspondinghydroxylamine [Va] using chloral hydrate and NH₂OH.HCl. Reaction ofcompound [Va] with a strong acid such as H₂SO₄ results in thepreparation of cyclic isatin [Wa]. The isatin ring of [Wa] is thencleaved using H₂O₂. The resultant acid [Xa] is converted toquinazolinedione [Ya] using urea. Quinazolinedione [Ya] is thenchlorinated at the 2- and 4-positions to form compound [Za] usingchlorinating agents. The 4-position of quinazoline [Za] is thensubstituted by reaction with an optionally substituted morpholine orthiomorpholine (R⁴) to afford compound [AAa]. The 8-position ofquinazoline compound [AA] is then R³-substituted by coupling with areagent such as R³B(OR)₂, R²SnBu₃, R²MgCl, or R²ZnCl. Finally,intermediate [BB] is reacted with intermediate [1].

Scheme 6B provides one synthetic route to compounds which areencompassed by formula (I), where R⁴ may be morpholine. In this route,3-bromoaniline is converted to the corresponding hydroxylamine [V1]using chloral hydrate, NH₂OH.HCl, Na₂SO₄, and hydrochloric acid in waterat about 90° C. for about 2 h. Reaction of compound [V1] with H₂SO₄ atelevated temperatures results in the preparation of cyclic isatin [W1].The isatin ring of [W1] is then cleaved using aqueous H₂O₂ and NaOH at0° C. for 2 h. The resultant amino benzoic acid [X1] is converted toquinazolinedione [Y1] using urea (10 eq) at about 200° C. for about 3 h.Quinazolinedione [Y1] is then chlorinated using POCl₃ and DIPEA at about130° C. for about 12 h to form compound [Z1]. The 4-position ofquinazoline [Z^(1]) is then substituted with morpholine by reaction withmorpholine in a solvent such as DCM at reduced temperatures of about 0°C. for about 15 min to afford compound [AA1]. The 7-position ofquinazoline compound [AA1] is then R²-substituted using R²B(OR)₂,PdCl₂(PPh₃)₂ (0.05 eq), Na₂CO₃ (1.5 eq), DMF, H₂O at 90° C. for 2-3 h.Finally, compound (VIc) is prepared by reacting intermediate [BB1] withintermediate [1] using PdCl₂(PPh₃)₂ (0.05 eq) and Cs₂CO₃ (2 eq) atelevated temperatures of about 90° C. over a period of about 2-3 hoursThe reaction may occur in DMF/H₂O or toluene/ethanol/H₂O, Scheme 6B mayalso be performed using compound [Ua] in place of compound [U1] toprovide additional compounds encompassed by generic formula (I).

Scheme 6C provides the synthesis of 2,4,7-tri-substituted quinazolinecompounds, which are encompassed by the compound of formula (I) when X—Zare CH, R¹ and R³ are H, R⁴ may be morpholine, R⁵ is H, and R⁶ is F.Specifically, steps a-g of this scheme are identical to steps a-g ofScheme 6 and thereby provide compound [BB1]. Reaction of intermediate[BB1] with intermediate [1] progresses using PdCl₂(PPh₃)₂ (0.05 eq) andCs₂CO₃ (2 eq) at elevated temperatures of about 90° C. over a period ofabout 2-3 hours in DMF/H₂O or toluene/ethanol/H₂O, Scheme 6C may also beperformed using compound [Ua] in place of compound [U1] to provideadditional compounds encompassed by generic formula (I).

Scheme 6D provides a the synthesis of 2,4,7-tri-substituted quinazolinecompounds which are encompassed by formula (I), where X—Z are CH, R¹,R³, and R⁶ are H, R⁴ may be morpholine, and R⁵ is F. Specifically, stepsa-g of this scheme are identical to steps a-g of Schemes 6 and 6A andthereby provide compound [BB1]. Reaction of intermediate [BB1] withintermediate [2B] progresses using PdCl₂(PPh₃)₂ (0.05 eq) and Cs₂CO₃ (2eq) at about 90° C. over a period of about 2-3 hours in DMF/H₂O ortoluene/ethanol/H₂O, Scheme 6D may also be performed using compound [Ua]in place of compound [U1] to provide additional compounds encompassed bygeneric formula (I).

Scheme 6E provides the synthesis of 2,4,7-tri-substituted quinazolinecompounds which are encompassed by formula (I), where X and Z are CH, Yis N, and R′, R³, R⁵, and R⁶ are H, and R⁴ may be morpholine.Specifically, steps a-g to form compound [BB1] may be performed usingthe reagents and conditions outlined in Scheme 6. Compound [BB1] maythen be converted to compound [KK1] using 2-aminopyridine-5-boronic acidpinacol ester, PdCl₂(PPh₃)₂, Cs₂CO₃, DMF, and H₂O at 90° C. for about2-3 h. Compound [LL1] may be prepared by reacting compound [KK1] withCl₃CCH₂OCOCl, TEA, CH₂Cl₂ at 0° C. to rt for about 5 h. Compound [LL1]is then converted to the title compound using an appropriatelysubstituted aniline such as 4-amino-N,N-dimethylbenzamide in a sealedtube in toluene at 110° C. for about 10 to about 15 h, such as about 10h. Scheme 6E may also be performed using compound [Ua] in place ofcompound [U1] to provide additional compounds encompassed by genericformula (I).

Scheme 6F provides the synthesis of 2,4,7-tri-substituted quinazolinecompounds which are encompassed by formula (I), where R¹, R², R⁵, and R⁶are H and R⁴ may be morpholine. This scheme is performed according tothe procedure of Scheme 6, but using compound [MM] instead of compound[U].

Scheme 6G provides the synthesis of 2,4,6,7-quinazoline compounds whereR¹ is F, R³ is H, and R⁴ in formula (I) may be morpholine. Specifically,steps a-h are performed as described in Scheme 6, but using compound[UU] instead of compound [U]. In one embodiment, compound [UU] isreacted with chloral hydrate, NH₂OH.HCl, Na₂SO₄, hydrochloric acid inwater at about 90° C. for about 2 h to provide oxime [VV]. Addition ofcompound [VV] at 50° C. to H₂SO₄ at about 90° C. for about 2 h providedisatin [WW]. The isatin [WW] ring is opened using aqueous H₂O₂ and NaOHat about 0° C. over about 2 h to form acid [XX]. Cyclization of acid[XX] to form quinazolinedione [YY] is performed using urea (10 eq) atabout 200° C. for about 3 h. Chlorination of compound [YY] is performedusing POCl₃ and DIPEA at about 130° C. for about 12 h to formintermediate [ZZ]. Substitution at the 4-position occurs usingmorpholine in CH₂Cl₂ at about 0° C. for about 15 min to form compound[AAA]. Reaction of compound [AAA] with R²B(OR)₂, PdCl₂(PPh₃)₂ (0.05 eq),Na₂CO₃ (1.5 eq), DMF, and H₂O at about 90° C. for about 2-3 h providescompound [BBB]. Finally, compound [BBB] is reacted with compound [1],PdCl₂(PPh₃)₂ (0.05 eq), Cs₂CO₃ (2 eq), in DMF/H₂O or toluene/ethanol/H₂Oat about 90° C. for about 2-3 h. Scheme 6G may be performed using2-bromo-4-fluoroaniline in place of compound [UU] to provide additionalcompounds encompassed by generic formula (I).

Scheme 7 provides the preparation of 2,4,7-pyrido-pyrimidine compoundswhich are encompassed by formula (I), where X is N, Y and Z are CH, andR¹ and R³ are H. Specifically, 5-bromo-3-nitro-picolinonitrile [CC] isconverted to the corresponding amide [DD] using Raney Nickel and H₂.Amide [DD] is then converted to the corresponding acid [EE] using abase. Reaction of compound [EE] with a reagent such as urea results inthe formation of compound [FF]. Chlorination of compound [FF] may beformed using a chlorinating agent. Substitution at the 4-position may beperformed using an optionally substituted morpholine or thiomorpholineto result in compound [HH]. Substitution of the 7-position of compound[HH] to form compound [JJ] may be accomplished by coupling with areagent such as R²B(OR)₂, R²SnBu₃, R²MgCl, or R²ZnCl and a catalyst.Finally, compound [JJ] is reacted with compound [1], PdCl₂(PPh₃)₂ (0.05eq), Cs₂CO₃ (2 eq), in DMF/H₂O or toluene/ethanol/H₂O at about 90° C.for about 2-3 h to form the noted compound. Scheme 7 may be performedusing 2-cyano-3-nitro-4-bromo-6-R¹-pyridine in place of compound [CC] toprovide additional compounds encompassed by generic formula (I).

In one embodiment, Scheme 7A provides the preparation of compounds whichare encompassed by formula (I). In this scheme,5-bromo-3-nitro-picolinonitrile [CC1] is converted to the correspondingamide [DD1] using Raney Nickel and H₂ in ethanol for about 14-20 h.Amide [DD1] is then converted to the corresponding acid [EE1] using NaOHin H₂O at about 110° C., followed up by work-up in dilute HCl. Reactionof compound [EE1] with urea at elevated temperatures results in theformation of compound [FF1]. Chlorination of compound [FF1] may beperformed using POCl₃ at elevated temperatures. Substitution at the4-position may be performed using morpholine to result in compound[HH1]. Substitution of the 7-position of compound [HH1] with R² to formcompound [JJ1] may be accomplished using R²B(OR)₂ and a catalyst such asPdCl₂(PPh₃)₂ in solvent systems such as DMF/H₂O or toluene/ethanol/H₂O.Finally, compound [JJ1] is reacted with compound [1], PdCl₂(PPh₃)₂ (0.05eq), Cs₂CO₃ (2 eq), in DMF/H₂O or toluene/ethanol/H₂O at about 90° C.for about 2-3 h to form the noted compound. Scheme 7A may be performedusing 5-bromo-3-nitro-picolinonitrile in place of compound [CC1] toprovide additional compounds encompassed by generic formula (I).

In another embodiment, Scheme 7B provides the preparation of2,4,7-trisubstituted pyrido-pyrimidine compounds which are encompassedby formula (I), where X is N, Y and Z are CH, and R¹, R³, and R⁶ are H.Specifically, 2-cyano-3-nitro-5-bromopyridine [CC1] is converted to thecorresponding amide [DD1] using Raney Nickel and H₂. Desirably, thereaction is performed in the presence of ethanol for about 14-20 h.Amide [DD1] is then converted to the corresponding acid [EE1] using NaOH(5 eq) and H₂O at about 110° C. for about 5 h, followed by work-up usingdil. HCl. Acid [EE1] is cyclized using urea (10 eq) at about 200° C. forabout 3 h to form pyrido-pyrimidine intermediate [FF1]. Intermediate[FF1] is reacted with POCl₃ and DIPEA at about 130° C. for about 10 h.The 4-position of the pyrido-pyrimidine is then substituted usingmorpholine in CH₂Cl₂ at a temperature of about 0° C. for about 30 min toform compound [HH1]. Compound [HH1] is then coupled with R² usingR²B(OR)₂, PdCl₂(PPh₃)₂ (0.05 eq), Na₂CO₃ (1.5 eq), DMF, and H₂O at about90° C. for about 2-3 h to form compound [JJ1]. The title compound isthen formed by reacting compound [JJ1] with PdCl₂(PPh₃)₂ for about 2-3h. Alternatively, the title compound may be formed by reactingintermediate [JJ1] with PdCl₂(PPh₃)₂ (0.05 eq) and Cs₂CO₃ (2 eq) intoluene, ethanol, and H₂O at a temperature of about 90° C. for about 2-3h.

In a further embodiment, Scheme 7C provides the synthesis of2,4,7-pyrido-pyrimidine compounds which are encompassed by formula (I),where X is N, Y and Z are CH, R² is aryl, and R¹, R³, R⁵, and R⁶ are H.This synthesis was performed according to the steps outlined in Scheme7B, with the exception that ArB(OR)₂ was utilized in place of R²B(OR)₂.Scheme 7C may be performed using 2-cyano-3-nitro-4-bromopyridine inplace of compound [CC1] to provide additional compounds encompassed bygeneric formula (I).

Scheme 8 provides another synthesis of 2,4,7-tri-substitutedquinazolines. In this scheme, diester aniline [CCC] is reacted with ureato form isatin [DDD]. Chlorination of the 2-position, followed bysubstitution of the 4-position with an optionally substituted morpholineor thiomorpholine (R⁴) affords compound [EEE]. Hydrolysis of the estermoiety of [EEE] affords acid [FFF]. The acid moiety of [FFF] is thenreacted with an amine to provide amide [GGG]. Finally reaction of amide[GGG] with compound [1] provides the final compound.

In one embodiment, diester aniline [CCC] is reacted with urea atelevated temperatures such as about 200° C. for about 3 h to provideisatin [DDD]. Yields of about 80% of compound [DDD] may be obtained.Chlorination at the 2- and 4-position of compound [DDD] may beaccomplished using POCl₃ and a base such as N,N-dimethyl aniline itDIPEA. In one embodiment, this reaction is performed at elevatedtemperatures such as about 120 to about 130° C., such as about 120° C.,for about 5 to about 6 h, such as about 5 h. An optionally substitutedmorpholine or thiomorpholine is then added in a solvent such as DCM. Inone embodiment, this reaction is performed at reduced temperatures suchas about 0° C. for about 15 to about 30 min, such as about 30 min, toprovide compound [EEE]. Yields of about 70% of compound [EEE] may beobtained. Hydrolysis of the ester moiety of compound [EEE] may beperformed using a weak base such as LiOH or NaOH in a solvent such asTHF:MeOH:H₂O (1:1:1). In one embodiment, this hydrolysis is performed atabout ambient temperature, such as about 25 to about 30° C., for about 1to about 3 h, such as about 1 h. By doing so, yields of about 80% ofcompound [FFF] may be obtained. Reaction of the acid moiety of compound[FFF] may be performed using an amine such asN,N-dimethylethylenediamine in the presence of DIPEA and HATU.Desirably, the reaction is performed in a solvent such as DMF for anextended period of time, e.g., overnight, to provide amide [GGG]. Yieldsof about 70% of amide [GGG] may be obtained. Finally, reaction of amide[GGG] with intermediate compound [1] provides the final product. In oneembodiment, amide [GGG] is reacted in the presence of a catalyst such asPdCl₂(PPh₃)₂ or Pd(PPh₃)₄, Cs₂CO₃, Na₂CO₃, or K₂CO₃, and a solventsystem such as DMF/water or toluene/ethanol/water. Desirably, thereaction is performed at elevated temperatures of about 80 to about 110°C., such as about 95° C., for an extended period of time including about5 to about 8 h, such as about 5 h. Yields of about 50% of the titlecompound may be obtained.

Scheme 8A provides the synthesis of compounds encompassed by formula(I). In this scheme, diester aniline [CCC1] is reacted with urea atabout 200° C. for about 3 h to provide isatin [DDD1]. Chlorination atthe 2- and 4-position of compound [DDD] may be accomplished using POCl₃and N,N-dimethyl aniline at about 120° C. for about 5 h. Morpholine isthen added in DCM at about 0° C. for about 30 min to provide compound[EEE1]. Hydrolysis of the ester moiety of compound [EEE1] may beperformed using LiOH in THF:MeOH:H₂O (1:1:1) at rt for about 1 h.Compound [FFF1] is reacted with N,N-dimethylethylenediamine, DIPEA,HATU, and DMF overnight to provide amide [GGG1]. Finally, reaction ofamide [GGG1] withN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)benzamide,PdCl₂(PPh₃)₂, and Cs₂CO₃, in DMF at about 95° C. for 5 h provides thefinal product.

It will be apparent to those skilled in the art that compounds offormula (I), where M is amide group —N(R⁹)—C(O)R¹⁰, can be synthesizedby methodology similar to those methods described above, wherein M is anamide group of type —C(O)NR⁷R⁸. For example, the boronic acid pinacolester intermediate compounds where M is amide group —N(R⁹)—C(O)R¹⁰ canbe prepared by methods similar to those described in Schemes 1, 2 and 5.For example, Scheme 9 depicts an example of the synthesis of boronicacid pinacol ester intermediate compound [2]. Specifically, a4-nitrobenzoic acid [A2] is converted to the corresponding amide [B2] byreaction with an acyl chloride R¹⁰COC1, in the presence of a base suchas TEA or DIPEA, and using a solvent such as DMF, THF, or DCM, typicallyat temperatures of 0 to 25° C., for about 30 minutes to 24 hours such as12 hours. The nitro-phenyl intermediate [B2] that is formed (R⁹═H inthis case) is then reduced to give the amino-phenyl intermediate [C2],for example by using hydrogen over catalytic 10% Pd/C, in a solvent suchas methanol or ethanol, for about 1 hour to 24 hours such as 12 hours.The intermediate [C2] is then converted to the urea [D] by methodsdescribed in Schemes 1 to 5 above, and urea [D2] is then converted tothe desired boronic acid pinacol ester compound [2] by methods describedin Schemes 1, 2 and 5. Additional compounds [2] are prepared from otherintermediates [C2] that can be synthesized by methods known to thoseskilled in the art, for example from halogen compounds [E]. As aspecific example, 1-(4-aminophenyl)pyrrolidin-2-one is used for thepreparation of compounds of formula (I) where M is an amide group oftype —N(R⁹)—C(O)R¹⁰, wherein R⁹ and R¹⁰ are joined such that —R⁹-R¹⁰— is—CH₂CH₂— to form a 1-pyrrolidinyl group. The intermediate [C2] which is1-(4-aminophenyl)pyrrolidin-2-one in this case, can be prepared byreaction of the compound [E] which is 4-iodoaniline in this case, with2-pyrrolidinone, in the presence of N,N′-ethylenediamine, CuI, and dryK₂CO₃, using 1,4-dioxane as solvent at 110° C., based on the methoddescribed in International Patent Publication No. WO-2006/055951.

The intermediate compounds [1] that are prepared by these variousmethods in Scheme 9 can be converted to compounds of formula (I), whereM is an amide group of type —N(R⁹)—C(O)R¹⁰, by using the couplingreaction methods that are described for Schemes 6, 7 and 8. Scheme 10depicts an example for the synthesis of compounds which are encompassedby the structure of formula (I), where R³ is H and M is an amide groupof type —N(R⁹)—C(O)R¹⁰. The synthetic method is similar to thatdescribed in Scheme 6, except that the final coupling step uses aboronic acid pinacol ester intermediate compound that is prepared asdescribed in Scheme 9.

It will be recognized by those skilled in the art that in certain casesthe groups R², R³, R⁷ and R⁸, as well as substituents on the groups R²,R³, R⁷ and R⁸, can be modified to produce different groups R², R³, R⁷and R⁸. The reactions to effect these modifications can be conductedduring the course of the synthetic sequences that are depicted inSchemes 1 to 8. Alternatively, in certain cases the groups R², R³, R⁷and R⁸, as well as substituents on the groups R², R³, R⁷ and R⁸, can bemodified after the preparation of compounds of the invention of formulaI, to produce additional compounds of formula I. Likewise, somesubstituents can be converted into hydrogen, to afford the correspondingderivative that is unsubstituted at that atom position. Examples of suchreactions to convert one substituent into a different substituentinclude, but are not limited to: the reduction of an aldehyde or estersubstituent to a hydroxymethylene group; the conversion of an aldehydeto form a secondary alcohol fragment; the conversion of an aldehyde orester group to form a dialkyl tertiary alcohol group; the conversion ofan aldehyde group to a methyl group; the conversion of an aldehyde groupto a methyl ester group and then (at a later step) to an amide orcarboxylic acid group; the conversion of an aldehyde group to adimethylamino-methylene fragment; the conversion of an aldehyde group toa cyano group; and the conversion of an aldehyde group to a methylketone fragment. Examples of these conversions and the reaction methodsthat can be used in these cases are depicted in Schemes 11 & 12.

In Scheme 11, intermediate [GGG2] is prepared by using the methodologydescribed in Schemes 6 and 7 (e.g., see Example 10, Step 1, in theExamples), and then methods a to h are applied to effect variousmodifications of the R² group. The resulting intermediates with thesedifferent R² groups are then converted to various compounds of theinvention of formula (I) by methods that are well-known to those skilledin the art, and the methods described in Schemes 6 and 7. Examples ofthe reagents and conditions used for steps a to h in Scheme 11 are asfollows: (a) NaBH₄, MeOH, rt, 1 h; (b) MeMgBr, THF, rt, 2 h; (c) i.NaCN, MnO₂, MeOH, 0° C.-rt, 3 h; ii. MeMgBr, THF, 0° C., 3 h; (d) i.NaCN, MnO₂, MeOH, 0° C.-rt, 3 h; (e) i. NaCN, MnO₂, MeOH, 0° C.-rt, 3 h;(f) NH(CH₃)₂.HCl, trimethyl orthoformate, NaCNBH₃, DCM, rt, 6 h; (g)NH₃(aq), I₂, acetonitrile, rt, 3 h; (h) i. MeMgBr, THF, rt, 2 h; ii.MnO₂, DCM, rt, 12 h.

In Scheme 12, intermediate [GGG3] is prepared by using the methodologydescribed in Scheme 8, and then methods a and b are applied to effectmodifications of the R² group. The resulting intermediates with thesedifferent R² groups are then converted to compounds of formula (I) bymethods described in Schemes 6. Examples of the reagents and conditionsused for steps a and b in Scheme 12 are: (a) LiAlH₄, THF, 0° C.-rt, 5 h;(b) MeMgBr, THF, 0° C.-rt, 12 h.

Scheme 13 depicts the preparation of boronic acid pinacol esterintermediate [3], in which the synthetic methodology is similar to thatused as described in Scheme 4, after the initial formation of the ester[B3] from the carboxylic acid [A]. The ester [B3] can be prepared byvarious methods known to those skilled in the art, such as by reactionof the acid [A] with methyl iodide in the presence of potassiumcarbonate, for example in DMF at room temperature for 2 hours. Reductionof the nitro group in [B3] to give intermediate [C3] is followed bysteps c and d to provide the urea intermediate [O3] via thetrichloroethyl carbamate intermediate [P3]. Alternatively, in certaincases the intermediate [C3] can be converted in one step to the ureaintermediate [O3], by treatment with the appropriate isocyanate, forexample by the method as described in Scheme 5. Conversion of urea [03]to intermediate [3] is accomplished by using the same reagents andconditions as described in step e of Scheme 4.

As depicted in Scheme 14, the intermediate [BB1] from Scheme 6B, [BBB]from Scheme 6G, [JJ1] from Scheme 7A or [EEE1] from Scheme 8A can betreated with compound [1] in Scheme 13 by using PdCl₂(PPh₃)₂, Cs₂CO₃,DMF, H₂O at 90-95° C. for 2-3 h, or PdCl₂(PPh₃)₂, Cs₂CO₃, toluene,ethanol and H₂O at 90-95° C., for 2-3 h. The obtained ester intermediate[4] is then hydrolysed, for example using lithium hydroxide in methanol,THF and H₂O, at rt for 5-12 h. The resulting acid intermediate is thensubjected to amide coupling with the appropriate amine R⁷R⁸NH, usingamide coupling conditions that are well known to those skilled in theart, such as HATU, with DIPEA or TEA, in DMF at rt for 12 h; orEDCI.HCl, with HOBt, and DIPEA or TEA, in DMF at rt for 12 h to obtainthe desired compounds encompassed by formula (I).

The method described in Scheme 15, which is similar to the methodsdepicted in Schemes 6 and 7, is used to prepare certain compounds offormula (I), where R¹ is H or methoxy, R² is H or methoxy, and X is H orF. Examples of the reagents and reaction conditions include, withoutlimitation, (a) urea, 200° C., 2-3 h; (b) POCl₃, DIPEA, 130° C., 4-12 h;or POCl₃, DIPEA, toluene, 130° C., 4-12 h; (c) morpholine, DCM, 0° C.,15 min; or morpholine, DCM, 0° C. to rt, 15 min-4 h; (d) substitutedurea boronic acid pinacol borate ester intermediate, PdCl₂(PPh₃)₂,Cs₂CO₃, DMF, H₂O, 90-95° C., 2-3 h; or substituted urea boronic acidpinacol borate ester, PdCl₂(PPh₃)₂, Cs₂CO₃, toluene, ethanol, H₂O,90-95° C., 2-3 h.

Pharmaceutical compositions useful herein contain a compound of formula(I) in a pharmaceutically acceptable carrier optionally with otherpharmaceutically inert or inactive ingredients. In another embodiment, acompound of formula (I) is present in a single composition. In a furtherembodiment, a compound of formula (I) is combined with one or moreexcipients and/or other therapeutic agents as described below.

The pharmaceutical compositions of the invention comprise an amount of acompound of formula (I) or a pharmaceutically acceptable salt thereofthat is effective for regulating the PI3K/AKT/mTOR pathway in a subject.Specifically, the dosage of the compound of formula (I) to achieve atherapeutic effect will depend on the formulation, age, weight and sexof the patient and route of delivery. It is also contemplated that thetreatment and dosage of the compound of formula (I) may be administeredin unit dosage form and that one skilled in the art would adjust theunit dosage form accordingly to reflect the relative level of activity.The decision as to the particular dosage to be employed (and the numberof times to be administered per day) is within the discretion of theordinarily-skilled physician, and may be varied by titration of thedosage to the particular circumstances to produce the desiredtherapeutic effect. In one embodiment, the therapeutically effectiveamount is about 0.01 mg/kg to 10 mg/kg body weight. In anotherembodiment, the therapeutically effective amount is less than about 5g/kg, about 500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200mg/kg, about 100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 mg/kg,about 1 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about100 μg/kg, about 75 μg/kg, about 50 μg/kg, about 25 μg/kg, about 10μg/kg, or about 1 μg/kg. However, the therapeutically effective amountof the compound of formula (I) can be determined by the attendingphysician and depends on the condition treated, the compoundadministered, the route of delivery, the age, weight, severity of thepatient's symptoms and response pattern of the patient.

The therapeutically effective amounts may be provided on regularschedule, i.e., daily, weekly, monthly, or yearly basis or on anirregular schedule with varying administration days, weeks, months, etc.Alternatively, the therapeutically effective amount to be administeredmay vary. In one embodiment, the therapeutically effective amount forthe first dose is higher than the therapeutically effective amount forone or more of the subsequent doses. In another embodiment, thetherapeutically effective amount for the first dose is lower than thetherapeutically effective amount for one or more of the subsequentdoses. Equivalent dosages may be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every two weeks, about every three weeks, about every month,and about every two months. The number and frequency of dosagescorresponding to a completed course of therapy will be determinedaccording to the judgment of a health-care practitioner. Thetherapeutically effective amounts described herein refer to totalamounts administered for a given time period; that is, if more than onecompound of formula (I) or a pharmaceutically acceptable salt thereof isadministered, the therapeutically effective amounts correspond to thetotal amount administered.

The pharmaceutical compositions containing a compound of formula (I) maybe formulated neat or with one or more pharmaceutical carriers foradministration. The amount of the pharmaceutical carrier(s) isdetermined by the solubility and chemical nature of the compound offormula (I), chosen route of administration and standard pharmacologicalpractice. The pharmaceutical carrier(s) may be solid or liquid and mayincorporate both solid and liquid carriers. A variety of suitable liquidcarriers are known and may be readily selected by one of skill in theart. Such carriers may include, e.g., DMSO, saline, buffered saline,hydroxypropylcyclodextrin, and mixtures thereof. Similarly, a variety ofsolid carriers and excipients are known to those of skill in the art.The compounds of formula (I) may be administered by any route, takinginto consideration the specific condition for which it has beenselected. The compounds of formula (I) may, be delivered orally, byinjection, inhalation (including orally, intranasally andintratracheally), ocularly, transdermally, intravascularly,subcutaneously, intramuscularly, sublingually, intracranially,epidurally, rectally, and vaginally, among others.

Although the compound of formula (I) may be administered alone, it mayalso be administered in the presence of one or more pharmaceuticalcarriers that are physiologically compatible. The carriers may be in dryor liquid form and must be pharmaceutically acceptable. Liquidpharmaceutical compositions are typically sterile solutions orsuspensions. When liquid carriers are utilized for parenteraladministration, they are desirably sterile liquids. Liquid carriers aretypically utilized in preparing solutions, suspensions, emulsions,syrups and elixirs. In one embodiment, the compound of formula (I) isdissolved a liquid carrier. In another embodiment, the compound offormula (I) is suspended in a liquid carrier. One of skill in the art offormulations would be able to select a suitable liquid carrier,depending on the route of administration. The compound of formula (I)may alternatively be formulated in a solid carrier. In one embodiment,the composition may be compacted into a unit dose form, i.e., tablet orcaplet. In another embodiment, the composition may be added to unit doseform, i.e., a capsule. In a further embodiment, the composition may beformulated for administration as a powder. The solid carrier may performa variety of functions, i.e., may perform the functions of two or moreof the excipients described below. For example, solid carrier may alsoact as a flavoring agent, lubricant, solubilizer, suspending agent,filler, glidant, compression aid, binder, disintegrant, or encapsulatingmaterial.

The composition may also be sub-divided to contain appropriatequantities of the compound of formula (I). For example, the unit dosagecan be packaged compositions, e.g., packeted powders, vials, ampoules,prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compoundof formula (I) include, without limitation, adjuvants, antioxidants,binders, buffers, coatings, coloring agents, compression aids, diluents,disintegrants, emulsifiers, emollients, encapsulating materials,fillers, flavoring agents, glidants, granulating agents, lubricants,metal chelators, osmo-regulators, pH adjustors, preservatives,solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspendingagents, syrups, thickening agents, or viscosity regulators. See, forexample, the excipients described in the “Handbook of PharmaceuticalExcipients”, 5^(th) Edition, Eds.: Rowe, Sheskey, and Owen, APhAPublications (Washington, D.C.), Dec. 14, 2005, which is incorporatedherein by reference.

In one embodiment, the compositions may be utilized as inhalants. Forthis route of administration, compositions may be prepared as fluid unitdoses using a compound of formula (I) and a vehicle for delivery by anatomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols,i.e., oral or intranasal. For this route of administration, thecompositions are formulated for use in a pressurized aerosol containertogether with a gaseous or liquefied propellant, e.g.,dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and thelike. Also provided is the delivery of a metered dose in one or moreactuations.

In another embodiment, the compositions may be administered by asustained delivery device. “Sustained delivery” as used herein refers todelivery of a compound of formula (I) which is delayed or otherwisecontrolled. Those of skill in the art know suitable sustained deliverydevices. For use in such sustained delivery devices, the compound offormula (I) is formulated as described herein.

In addition to the components described above for use in the compositionand the compound of formula (I), the compositions may contain one ormore medications or therapeutic agents which are used to treat solidtumors. In one embodiment, the medication is a chemotherapeutic.Examples of chemotherapeutics include those recited in the “Physician'sDesk Reference”, 64^(th) Edition, Thomson Reuters, 2010, which is herebyincorporated by reference. Therapeutically effective amounts of theadditional medication(s) or therapeutic agents are well known to thoseskilled in the art. However, it is well within the attending physicianto determine the amount of other medication to be delivered.

The compounds of formula (I) and/or other medication(s) or therapeuticagent(s) may be administered in a single composition. However, thepresent invention is not so limited. In other embodiments, the compoundsof formula (I) may be administered in one or more separate formulationsfrom other compounds of formula (I), chemotherapeutic agents, or otheragents as is desired.

Also provided herein are kits or packages of pharmaceutical formulationscontaining the compounds of formula (I) or compositions describedherein. The kits may be organized to indicate a single formulation orcombination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound offormula (I) formulated for the desired delivery route. Suitably, the kitcontains instructions on dosing and an insert regarding the activeagent. Optionally, the kit may further contain instructions formonitoring circulating levels of product and materials for performingsuch assays including, e.g., reagents, well plates, containers, markersor labels, and the like. Such kits are readily packaged in a mannersuitable for treatment of a desired indication. For example, the kit mayalso contain instructions for use of a spray pump or other deliverydevice. Other suitable components to include in such kits will bereadily apparent to one of skill in the art, taking into considerationthe desired indication and the delivery route.

The compounds of formula (I) or compositions described herein can be asingle dose or for continuous or periodic discontinuous administration.For continuous administration, a package or kit can include the compoundof formula (I) in each dosage unit (e.g., solution, lotion, tablet,pill, or other unit described above or utilized in drug delivery), andoptionally instructions for administering the doses daily, weekly, ormonthly, for a predetermined length of time or as prescribed. When thecompound of formula (I) is to be delivered periodicallyin adiscontinuous fashion, a package or kit can include placebos duringperiods when the compound of formula (I) is not delivered. When varyingconcentrations of a composition, of the components of the composition,or the relative ratios of the compounds of formula (I) or agents withina composition over time is desired, a package or kit may contain asequence of dosage units which provide the desired variability.

A number of packages or kits are known in the art for dispensingpharmaceutical agents for periodic oral use. In one embodiment, thepackage has indicators for each period. In another embodiment, thepackage is a labeled blister package, dial dispenser package, or bottle.

The packaging means of a kit may itself be geared for administration,such as an inhalant, syringe, pipette, eye dropper, or other suchapparatus, from which the formulation may be applied to an affected areaof the body, such as the lungs, injected into a subject, or even appliedto and mixed with the other components of the kit.

The compositions of these kits also may be provided in dried orlyophilized forms. When reagents or components are provided as a driedform, reconstitution generally is by the addition of a suitable solvent.It is envisioned that the solvent also may be provided in anotherpackage.

The kits of the present invention also will typically include a meansfor containing the vials in close confinement for commercial sale suchas, e.g., injection or blow-molded plastic containers into which thedesired vials are retained. Irrespective of the number or type ofpackages and as discussed above, the kits also may include, or bepackaged with a separate instrument for assisting with theinjection/administration or placement of the composition within the bodyof an animal. Such an instrument may be an inhalant, syringe, pipette,forcep, measuring spoon, eye dropper or any such medically approveddelivery means.

In one embodiment, a kit is provided and contains a compound of formula(I). The compound of formula (I) may be in the presence or absence ofone or more of the carriers or excipients described above. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease characterized bythe dysregulation of the PI3K/AKT/mTOR pathway.

In a further embodiment, a kit is provided and contains a compound offormula (I) in a second dosage unit, and one or more of the carriers orexcipients described above in a third dosage unit. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease characterized bythe dysregulation of the PI3K/AKT/mTOR pathway.

The compounds described herein are useful in regulating conditions whichare associated with the PI3K/AKT/mTOR pathway. In one embodiment, such adisease is associated with abnormal cellular proliferation. The term“abnormal cellular proliferation” refers to the uncontrolled growth ofcells which are naturally present in a mammalian body. In oneembodiment, a disease which is characterized by abnormal cellularproliferation is cancer, including, without limitation, cancer of theprostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx,pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus,cervix, breast, ovaries, vagina, testicles, skin, thyroid, blood, lymphnodes, kidney, liver, intestines, pancreas, brain, central nervoussystem, adrenal gland, or skin or a leukemia. In one embodiment, thedisease characterized by abnormal cellular proliferation is cancer ofthe prostate.

The compounds of formula (I) regulate activity of mTOR and of PI3K. In afurther embodiment, the compounds of formula (I) regulate PI3K activity.The tested compounds of formula (I) have the ability to inhibit all fourisoforms of PI3K (α, β, δ, γ) with at least two of the compounds showingselectivity for the α PI3K isoform. These compounds associated withselective activity for the α isoform may be particularly well suited fortreatment of conditions associated with the PI3K isoform, including,e.g., breast and gastric cancers, colorectal tumors, glioblastomas, andprostate cancer, and lung cancers.

In another embodiment, the compounds of formula (I) regulate the pathwayof the PI3K-β isoform. In still a further embodiment, the compounds offormula (I) regulate the pathway of the PI3K-δ isoform. In yet anotherembodiment, the compounds of formula (I) regulate the pathway of thePI3K-γ isoform.

The ability of compounds to inhibit the PI3K delta and PI3K gammaisoforms has been described with the ability to treat acute and chronicinflammatory disorders. See, e.g., R C Camps et al, Nat Rev Immunol.,2007, Mar. 7(3): 191-201. Other inflammatory disorders have beenassociated more specifically with the PI3K delta isoform, includingneutrophil-associated inflammation. Models for testing the ability ofcompounds to reduce inflammation in inflammatory arthritis are known,e.g., as described by Camps et al, Nature Med., 2005, 11, 936-943. Campset al (2005) also describes models useful in assessing the ability ofcompounds to reduce inflammation in peritonitis. Models for testing theability of compounds to reduce inflammation and/or improve healing aftermyocardial infarction are described by Siragusa et al, Circ. Res.(2010), 106, 757-768. A model for testing the ability of compounds toprevent bleomycin-induced pulmonary fibrosis is described by Wei et al,Biochem Biophys Res Comm. 2010, 397: 311-317 and Brent et al,Toxicology, 2000, 147: 1-13.

The term “regulation” or variations thereof as used herein refers to theability of a compound of formula (I) to inhibit one or more componentsof a biological pathway. In one embodiment, “regulation” refers toinhibition of mTOR activity. In another embodiment, “regulation” refersto inhibition of PI3K activity. In a further embodiment, regulationrefers to dual inhibition of mTOR and PI3K activity.

The utility of the compounds of formula (I) can be illustrated, forexample, by their activity in the in vitro tumor cell proliferationassay described below. The compounds of formula (I) exhibit an mTOR andPI3K inhibitory activity, and therefore can be utilized in order toinhibit abnormal cell growth in which mTOR plays a role. Thus, thecompounds of formula (I) are effective in the treatment of disorderswith which abnormal cell growth actions of mTOR and/or PI3Kdysregulation are associated, such as cancer.

In one embodiment, methods for regulating the PI3K and/or mTOR pathwaysare provided and include administering a therapeutically effectiveamount of a compound of formula (I) to a patient in need thereof.

In another desirable embodiment, methods for treating a diseasecharacterized by an abnormal cellular growth resulting from adysregulated PI3K/mTOR pathway are provided and include administering ofa therapeutically effective amount of a compound of formula (I) to apatient in need thereof.

In a further desirable embodiment, methods for treating a conditiontreatable by inhibiting the PI3K/AKT/mTOR pathway are provided andinclude administering a therapeutically effective amount of a compoundof formula (I) to a patient in need thereof.

As described herein, a therapeutically effective amount of a compoundwhen used for the treatment of cancer is an amount which may reduce thenumber of cancer cells, reduce tumor size, inhibit metastasis, inhibittumor growth and/or ameliorate one or more of the symptoms of thecancer. For cancer therapy, efficacy can be measured for example, byassessing the time to disease progression and/or determining theresponse rate.

As described herein, a therapeutically effective amount of a compoundwhen used for the treatment of an inflammatory disorder is an amountwhich may delay the onset of or reduce the severity or duration of aninflammatory response, or which mitigates one or more symptoms of aninflammatory response. For treatment of an inflammatory disorder,efficacy can be measured, for example, by a reduction in physiologicsigns of inflammation (e.g., redness, swelling, heat, loss of function)or by measuring changes in the levels of cells (e.g., monocytes,macrophages and other mononuclear cells) or molecules (e.g.,pro-inflammatory cytokines) associated with inflammation.

The following examples are illustrative only and are not intended tolimit the present invention.

EXAMPLES

Unless otherwise stated, all the raw materials are purchased fromSigma-Aldrich, Fluorochem, Apollo Scientific and Matrix Labs andsolvents from Ranchem, S. D. Fine and Merck labs. ¹H NMR spectra wererecorded on Varian 300 and 400 MHz instruments, using TMS as internalreference. The chemical shift values are quoted in δ (parts permillion). Mass spectra of all the intermediates and final compounds wererecorded using Agilent® LC/MSD/VL and API 2000 LC/MS instruments using aSynergi™ 2.5μ MAX-RP column (100 Å Mercury; 20×4.0 mm), a mobile phaseof 0.1% formic acid in water and ACN, a flow rate of 2 mL/min, atemperature of 30° C., and a run time of 3.0 min. The purity of all thefinal compounds was detected using Agilent® HPLC 1100 & 1200 instrumentsand the following conditions:

Condition 1:

-   -   Column: AG/C18/25-008 (Zorbax® Eclipse XDB-C18 column, 4.6×250        mm, 5μ, mobile phase: A=0.01% TFA in water; B=ACN/MeOH (1:1);        gradient: 95:05; flow: 1.0 mL/min; temperature: 40° C.; run        time: 12 min

Condition 2:

-   -   Column: AG/C18/15-001 (Zorbax® Eclipse XDB-C18 column, 4.6×150        mm, 5μ, mobile phase: A=0.01% TFA in water; B=ACN/MeOH (1:1),        isocratic: 40:60, flow: 1.0 mL/min, temperature: 25° C., run        time: 12 min,

Condition 3:

-   -   Column: AG/C18/15-009 (Zorbax® Eclipse XDB-C18 column, 4.6×150        mm, 5μ, mobile phase: A=5 mM ammonium acetate in water; B: ACN,        gradient: 95:05, flow: 1.0 mL/min, temperature: 40° C., run        time: 12.0 min

Preparation 1:N,N-Dimethyl-4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-benzamide

Step 1: N,N-dimethyl-4-nitro benzamide

To a solution of 4-nitro-benzoic acid (20 g, 0.1196 mol) in DMF (300 mL)N,N-dimethylamine hydrochloride (11.7 g, 0.1436 mol), HOBt (20.9 g,0.1554 mol), EDC.HCl (34.3 g, 0.1794 mol) and DIPEA (30.91 g, 0.2392mol) were added. The reaction mixture was stirred at room temperaturefor 12 h. The reaction mixture was diluted with water and extracted withethyl acetate (3×500 mL). The organic layer was washed with water, brineand dried over sodium sulfate. The solvent was evaporated under reducedpressure to afford the title compound [23.0 g, 99%]; LC-MS (ESI):Calculated mass: 194.1; Observed mass: 195.1 [M+H]⁺ (RT: 1.70 min).

Step 2: 4-Amino-N,N-dimethyl-benzamide

To a solution of N,N-dimethyl-4-nitro benzamide (23 g, 0.1185 mol) inMeOH (200 mL) was added Pd/C 10% (2.3 g) in portions and the Parrreaction vessel was purged with nitrogen for 10 min. The reaction vesselwas fixed in Parr shaker at 60 psi pressure for 3 h. The reactionmixture was filtered through the Celite® pad and the filtrate wasconcentrated under reduced pressure to afford the title compound [18.0g, 93%]; LC-MS (ESI): Calculated mass: 164.1; Observed mass: 165.2[M+H]⁺ (RT: 0.17 min).

Step 3: 4-[3-(4-Bromo-phenyl)-ureido]-N,N-dimethyl-benzamide

To a solution of 4-amino-N,N-dimethyl-benzamide (3.5 g, 0.0213 mol), TEA(2.15 g, 0.0213 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate(5.07 g, 0.0256 mol). The reaction mixture was stirred at roomtemperature for 12 h. The white solid was obtained and was filtered anddried to afford the title compound [6.8 g, 88%]; LC-MS (ESI): Calculatedmass: 361.0; Observed mass: 362.0 [M+H]⁺ (RT: 0.17 min).

Step 4:N,N-Dimethyl-4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-benzamide

To a solution of 4-[3-(4-bromo-phenyl)-ureido]-N,N-dimethyl-benzamide(6.8 g, 0.0187 mol) in 1,4-dioxane (350 mL) were addedbis(pinacolato)diboron (7.15 g, 0.0281 mol), KOAc (5.5 g, 0.0561 mol)and PdCl₂(dppf).DCM (1.0 g, 0.0013 mol). The reaction vessel was purgedwith nitrogen for 10 min. The reaction mixture was stirred at 105° C.for 12 h. The reaction mixture was diluted with water and extracted withethyl acetate [3×100 mL]. The organic layer was washed with water, brineand dried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude residue. The crude product was purifiedusing column chromatography (60-120 silica gel, 5% MeOH in chloroform)to yield the desired title product. [3.7 g, 48%]; ¹H NMR (300 MHz,DMSO-d₆): δ 8.91 (d, J=6.0 Hz, 2H), 7.43-7.61 (m, 6H), 2.95 (s, 6H),1.25 (s, 12H); LC-MS (ESI): Calculated mass: 409.2; Observed mass: 410.1[M+H]⁺ (RT: 1.5 min).

Preparation 2:N-(2-Dimethylamino-ethyl)-N-methyl-4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide

Step 1: N-(2-Dimethylamino-ethyl)-N-methyl-4-nitro benzamide

To a solution of 4-nitro-benzoic acid (3.0 g, 0.01795 mol) in DMF (40mL), N,N,N′-trimethyl ethylenediamine (2.2 g, 0.02154 mol), HOBt (3.15g, 0.02335 mol), EDC.HCl(5.16 g, 0.02692 mol) and DIPEA (4.64 g, 0.0359mol) were added. The reaction mixture was stirred at ambient temperaturefor 12 h. The reaction mixture was diluted with water and extracted withethyl acetate (3×100 mL). The organic layer was washed with water, brineand dried over sodium sulfate. The solvent was evaporated under reducedpressure to afford the title compound [4.5 g, 100%]; LC-MS (ESI):Calculated mass: 251.1; Observed mass: 251.9 [M+H]⁺ (RT: 0.21 min).

Step 2: 4-Amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide

To a solution of N-(2-dimethylamino-ethyl)-N-methyl-4-nitro benzamide(4.5 g, 0.0179 mol) in MeOH (100 mL) was added Pd/C 10% (0.5 g) inportions and the Parr reaction vessel was purged with nitrogen for 10min. The reaction vessel was fixed in Parr shaker at 60 psi pressure for3 h. The reaction mixture was filtered through the Celite® pad and thefiltrate was concentrated under reduced pressure to afford the titlecompound [4.0 g, 100%]; LC-MS (ESI): Calculated mass: 221.2; Observedmass: 222.1 [M+H]⁺ (RT: 0.17 min).

Step 3:4-[3-(4-Bromo-phenyl)-ureido]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide

To a solution of 4-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide(4.0 g, 0.01809 mol) and TEA (2.01 g, 0.01809 mol) in DCM (50 mL) wasadded 4-bromophenyl isocyanate (4.3 g, 0.0217 mol). The reaction mixturewas stirred at room temperature for 12 h. The white solid was obtainedand was filtered and dried to afford the title compound [5.0 g, 67%];LC-MS (ESI): Calculated mass: 418.1; Observed mass: 421.1 [M+H]⁺ (RT:1.23 min).

Step 4:N-(2-Dimethylamino-ethyl)-N-methyl-4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide

To a solution of4-[3-(4-bromo-phenyl)-ureido]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide(5.0 g, 0.0119 mol) in 1,4-dioxane (250 mL) were added bis(pinacolato)diboron (4.5 g, 0.01789 mol), KOAc (3.5 g, 0.0357 mol) andPdCl₂(dppf).DCM (0.681 g, 0.00083 mol). The reaction vessel was purgedwith nitrogen for 10 min. The reaction mixture was stirred at 105° C.for 12 h. The reaction mixture was diluted with water and extracted withethyl acetate [3×100 mL]. The organic layer was washed with water, brineand dried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude residue. The crude product was purifiedusing column chromatography (60-120 silica gel, 40% MeOH in chloroform)to get the desired product [0.5 g, 9%]; ¹H NMR (300 MHz, DMSO-d₆): δ7.66-7.72 (m, 4H), 7.46-7.60 (m, 3H), 7.28-7.32 (m, 1H), 4.01 (d, J=6.6Hz, 4H), 2.94 (s, 3H), 1.80-1.98 (m, 6H), 1.28 (s, 12H); LC-MS (ESI):Calculated mass: 466.3; Observed mass: 467.2 [M+H]⁺ (RT: 0.62 min).

Preparation 3:1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea

Step 1: (4-Methyl-piperazin-1-yl)-(4-nitro-phenyl)-methanone

To a solution of 4-nitro-benzoic acid (10 g, 0.0598 mol) in DMF (300 mL)1-methyl-piperazine (7.19 g, 0.0718 mol), HOBt (10.5 g, 0.0777 mol),EDC.HCl (17.12 g, 0.0897 mol) and TEA (12.1 g, 0.1196 mol) were added.The reaction mixture was stirred at room temperature for 12 h. Thereaction mixture was diluted with water and extracted with ethyl acetate(3×200 mL). The organic layer was washed with water, brine and driedover sodium sulfate. The solvent was evaporated under reduced pressureto afford the title compound [14 g, 95%]; LC-MS (ESI): Calculated mass:249.1; Observed mass: 250.0 [M+H]⁺ (RT: 0.10 min).

Step 2: (4-Amino-phenyl)-(4-methyl-piperazine-1-yl)-methanone

To a solution of (4-Methyl-piperazin-1-yl)-(4-nitro-phenyl)-methanone(14 g, 0.05623 mol) in MeOH (100 mL) was added Pd/C 10% (1.4 g) inportions and the Parr reaction vessel was purged with nitrogen for 10min. reaction vessel was fixed in Parr shaker at 60 psi pressure for 3h. The reaction mixture was filtered through the Celite® pad and thefiltrate was concentrated under reduced pressure to afford the titlecompound [11 g, 89%]; LC-MS (ESI): Calculated mass 219.1; Observed mass:220.1 [M+H]⁺ (RT: 0.16 min).

Step 3:1-(4-Bromo-phenyl)-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea

To a solution of (4-amino-phenyl)-(4-methyl-piperazine-1-yl)-methanone(10.0 g, 0.0456 mol) and TEA (4.7 g, 0.0456 mol) in DCM (150 mL) wasadded 4-bromophenyl isocyanate (10.9 g, 0.0547 mol). The reactionmixture was stirred at room temperature for 12 h. The white solid wasobtained and was filtered and dried to afford the title compound [15.0g, 79%]; LC-MS (ESI): Calculated mass: 416.1; Observed mass: 417.1[M+H]⁺ (RT: 0.23 min).

Step 4:1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea

To a solution of1-(4-bromo-phenyl)-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea(2.5 g, 0.006 mol) in 1,4-dioxane (60 mL). were added bis(pinacolato)diboron (2.2 g, 0.0089 mol), KOAc (1.76 g, 0.01797 mol) andPdCl₂(dppf).DCM (0.34 g, 0.00041 mol). The reaction vessel was purgedwith nitrogen for 10 min. The reaction mixture was stirred at 105° C.for 12 h. The reaction mixture was diluted with water and extracted withethyl acetate [3×100 mL]. The organic layer was washed with water, brineand dried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude residue. The crude product was purifiedusing column chromatography (60-120 silica gel, 15% MeOH in chloroform)to yield the desired title product [0.9 g, 32%]; ¹H NMR (300 MHz,DMSO-d₆): δ 8.76 (s, 1H), 8.48 (s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.45 (d,J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 3.34-3.36(m, 4H) 3.05-3.08 (m, 4H), 2.26 (s, 3H), 1.26 (s, 12H); LC-MS (ESI):Calculated mass: 464.3; Observed mass: 465.1 [M+H]⁺ (RT: 0.61 min).

Preparation 4:4-{3-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-N,N-dimethyl-benzamide

Step 1: 4-[3-(4-Bromo-2-fluoro-phenyl)-ureido]-benzoic acid ethyl ester

To a solution of 4-bromo-2-fluoroaniline (0.5 g, 0.0026 mol) and TEA(0.38 mL, 0.0026 mol) in DCM (15 mL) was added ethyl4-isocyanatobenzoate (0.503 g, 0.0026 mol). The reaction mixture wasstirred at room temperature for 3 h. The white solid was obtained andwas filtered and dried to afford the title compound [0.7 g, 70%]; LC-MS(ESI): Calculated mass: 380.0; Observed mass: 381.0 [M+H]⁺ (RT: 1.78min).

Step 2: 4-[3-(4-Bromo-2-fluoro-phenyl)-ureido]-benzoic acid

To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acidethyl ester (0.7 g, 0.0018 mol) in EtOH (5 mL) and THF (4 mL), was addeda solution of lithium hydroxide monohydrate in water (0.385 g, 0.009mol, in 5 mL water) at room temperature. The reaction mass was stirredat room temperature for 5 h. The volatiles were evaporated under reducedpressure. The white solid was washed with diethyl ether. Subsequently,the reaction mixture was acidified with 2 N HCl [pH-6] at 0° C. toafford the solid compound. The solid material was collected byfiltration and dried to obtain the title compound [0.55 g, 84%]; LC-MS(ESI): Calculated mass: 352.0; Observed mass: 352.9 [M+H]⁺ (RT: 1.49min).

Step 3: 4-[3-(4-Bromo-2-fluoro-phenyl)-ureido]-N,N-dimethyl-benzamide

To a solution of 4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-benzoic acid(0.5 g, 0.014 mol) in DMF (5 mL) N,N-dimethylamine hydrochloride (0.14g, 0.0017 mol), HOBt (0.25 g, 0.0.0018 mol), EDC.HCl (0.41 g, 0.0021mol) and TEA (0.4 mL, 0.0028 mol) were added. The reaction mixture wasstirred at room temperature for 10 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate (3×15 mL). The organic layerwas washed with water, brine and dried over sodium sulfate. The solventwas evaporated under reduced pressure to afford the title compound [0.33g, 65%]; LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.0 [M+H](RT: 1.41 min).

Step 4:4-{3-[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-N,N-dimethyl-benzamide

To a solution of4-[3-(4-bromo-2-fluoro-phenyl)-ureido]-N,N-dimethyl-benzamide (0.25 g,0.000658 mmol) in 1, 4-dioxane (10 mL) were added bis(pinacolato)diboron(0.25 g, 0.000987 mol), KOAc (0.19 g, 0.00193 mol) and PdCl₂(dppf).DCM(0.037 g, 0.000046 mol). The reaction vessel was purged with nitrogenfor 10 min. The reaction mixture was stirred at 105° C. for 12 h. Thereaction mixture was diluted with water and extracted with ethyl acetate[3×100 mL]. The organic layer was washed with water, brine and driedover sodium sulfate. The solvent was removed under reduced pressure toafford the crude residue. The crude product was purified using columnchromatography (60-120 silica gel, 5% MeOH in chloroform) to yield thedesired title product. [0.183 g, 65%]; ¹H NMR (300 MHz, DMSO-d₆): δ 9.34(s, 1H), 8.79 (s, 1H), 8.22-8.39 (m, 1H), 7.35-7.52 (m, 6H), 2.96 (s,6H), 1.29 (s, 12H); LC-MS (ESI): Calculated mass: 427.2; Observed mass:428.2 [M+H]⁺ (RT: 1.59 min)

Preparation 5: Synthesis of4-(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

Step 1: 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate

To a 250 mL round bottom flask, 4-amino-N,N-dimethyl-benzamide (20 g,0.1219 mol; prepared as described in Preparation 1) and2,2,2-trichloroethyl chloroformate (30 g, 0.1463 mol), TEA (34 mL,0.2438 mol) and DCM (100 mL) was added. The reaction mixture was stirredat room temperature for 1 h. The reaction mass was diluted with DCM andwashed with water. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to get the crude product.The crude product was washed with diethyl ether and dried under reducedpressure to afford the title compound [30 g, 73%]. LC-MS (ESI):Calculated mass: 338.0; Observed mass: 341.0 (RT: 1.38 min). Thecompound was directly taken to the next step.

Step 2: 4-(3-(4-bromo-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide

To a 250 mL round bottom flask,2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate (30 g, 0.0885mol), 4-bromo-3-fluoroaniline (20 g, 0.1062 mol), TEA (24.6 mL, 0.177mol) and toluene (150 mL) was added. The reaction mixture was maintainedat 110° C. for 12 h. The reaction mass was cooled to room temperature.The obtained precipitate was collected by filtration and dried undervacuum to get the desired product [15 g, 50%]. ¹H NMR (300 MHz,DMSO-d₆): δ 9.09 (s, 1H), 8.99 (s, 1H), 7.65-7.53 (m, 2H), 7.49 (d,J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 2.93 (s,6H); LC-MS (ESI): Calculated mass: 379.0; Observed mass: 382.1 (RT: 1.43min).

Step 3:4-(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

To a 500 mL round bottom flask,4-(3-(4-bromo-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide (15.0 g,0.0395), bis(pinacolato)diboron (15.19 g, 0.0593 mol), KOAc (7.7 g,0.0790 mol) and 1,4-dioxane (200 mL) was added. The reaction vessel wasdegassed with nitrogen for 5 min. To the flask was added Pd(dppf)Cl₂.DCM(2.2 g, 0.0027 mol) and again degassed with nitrogen for 5 min. Thereaction mixture was maintained at 115° C. for 12 h. The cooled reactionmass was filtered through a pad of Celite® reagent. Water was then addedto the filtrate and the product extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain the crude product. The crude productwas purified by column chromatography using 60-120 silica gel, 2-5% MeOHin chloroform to get the title compound [7 g, 43%]. ¹H NMR (400 MHz,CDCl₃): δ 8.56 (s, 1H), 8.23 (s, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.39 (dd,J″=1.6 Hz, J″=11.6 Hz, 1H), 7.21 (d, J=8.4 z, 2H), 7.07 (dd, J′=8.0 Hz,J″=1.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.18 (s, 3H), 3.02 (s, 3H), 1.35(s, 12H); LC-MS (ESI): Calculated mass: 427.2; Observed mass: 428.1 (RT:1.54 min).

Preparation 6:2-fluoro-N,N-dimethyl-4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-benzamideStep 1: 2-fluoro-N,N-dimethyl-4-nitro benzamide

To a 50 mL round bottom flask, 2-fluoro-4-nitrobenzoic acid (3.0 g,0.0162 mol) and DMF (10 mL) was added. To the same flask, TEA (4.6 mL,0.0324 mol), dimethylamine hydrochloride (2.65 g, 0.0324 mol), HOBt(3.28 g, 0.0243 mol) and EDCI.HCl(4.62 g, 0.0243 mol) was added. Thereaction mixture was stirred at room temperature for 12 h. The reactionmass was quenched with water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to get the title compound [2.8 g, 81%]. ¹H NMR(300 MHz, CDCl₃): δ 8.12 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.62(dd, J′=8.1 Hz, J″=6.6 Hz, 1H), 3.16 (s, 3H), 2.93 (s, 3H); LC-MS (ESI):Calculated mass: 212.1; Observed mass: 213.1 (RT: 0.37 min).

Step 2: 4-amino-2-fluoro-N,N-dimethyl-benzamide

To a 50 mL round bottom flask was added 2-fluoro-N,N-dimethyl-4-nitrobenzamide (2.8 g, 0.0132 mol) and EtOH (20 mL). To the same flask,SnCl₂.2H₂O (11.9 g, 0.0528 mol) was added and the reaction mixture wasmaintained at 85° C. for 2 h. The reaction mass was cooled to roomtemperature and the volatiles were evaporated under reduced pressure.The residue was dissolved in water and ethyl acetate. Aqueous saturatedsodium bicarbonate was added to adjust to a pH of 7.0. The reactionmixture was filtered through a pad of Celite® reagent and washed withethyl acetate. The organic layer was separated, dried over anhydroussodium sulfate and evaporated under reduced pressure to obtain the titlecompound [2.5 g, 100%]. ¹H NMR (300 MHz, CDCl₃): δ 7.21 (t, J=7.8 Hz,1H), 6.46 (dd, J′=8.4 Hz, J″=2.4 Hz, 1H), 6.34 (d, J′=11.4 Hz, J″=1.8Hz, 1H), 3.95 (brs, 2H), 3.08 (s, 3H), 2.95 (d, J=1.8 Hz, 3H); LC-MS(ESI): Calculated mass: 182.1; Observed mass: 183.1 (RT: 0.17 min).

Step 3: 4-(3-(4-bromophenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide

To a 100 mL round bottom flask, 4-amino-2-fluoro-N,N-dimethyl-benzamide(2.5 g, 0.0137 mol), 4-bromophenylisocyanate (3.3 g, 0.0164), TEA (3.9mL, 0.0274 mol) and DCM (50 mL) was added. The reaction mixture wasstirred at room temperature for 12 h. After 12 h, the precipitate wasformed and was collected by filtration. The solid was washed withdiethyl ether and dried to get the title compound [3.0 g, 58%].Calculated mass: 379.0; Observed mass: 380.0 (RT: 1.46 min). Thiscompound was directly taken to the next step.

Step 4:2-fluoro-N,N-dimethyl-4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-benzamide

To a 100 mL round bottom flask,4-(3-(4-bromophenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide (3.0 g,0.00789 mol), bis(pinacolato)diboron (3.02 g, 0.01179 mol), KOAc (2.32g, 0.02363 mol) and 1,4-dioxane (30 mL) were added and degassed withnitrogen for 5-10 min. To the flask, Pd(dppf)Cl₂.DCM (0.45 g, 0.0005513mol) was added and again degassed with nitrogen for 5-10 min. Thereaction mixture was maintained at 105° C. for 12 h. To the cooledreaction mass, water was added and extracted with ethyl acetate. Theethyl acetate layer was dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain the crude product. The crudeproduct was subjected to column chromatography using 60-120 silica geland 2-5% MeOH in chloroform to get the title compound [1.1 g, 33%]. ¹HNMR (300 MHz, DMSO-d₆): δ 8.41 (s, 1H), 8.23 (s, 1H), 7.74 (d, J=8.4 Hz,2H), 7.44 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.09 (t, J=8.1 Hz,1H), 6.55 (d, J=8.4 Hz, 1H), 3.16 (s, 3H), 2.91 (s, 3H), 1.33 (s, 12H);LC-MS (ESI): Calculated mass: 427.2; Observed mass: 428.2 (RT: 1.58min).

Preparation 7:4-(3-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

Step 1: 4-bromo-2,3-difluoroaniline

The procedure for preparing this compound was based on that described inInternational Patent Publication No. WO 2010/091272. To a 100 mL roundbottom flask, 2,3-difluoroaniline (1 g, 0.0077 mol) and ACN (30 mL) wereadded. To the flask was added the solution of tetrabutylammoniumtribromide (3.71 g, 0.0077 mol, in 10 mL of ACN). The reaction mixturewas stirred at room temperature for 3 h. The reaction mass was dilutedwith water and extracted with ethyl acetate. The ethyl acetate layer waswashed with brine and evaporated under reduced pressure to get the crudeproduct. The crude product was purified by column chromatography using60-12 silica gel and 30% ethyl acetate in hexane to get the titlecompound [0.55 g, 34%]. The obtained product was immediately taken tothe next step.

Step 2: 4-(3-(4-bromo-2,3-difluorophenyl)ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask, 4-bromo-2,3-difluoroaniline (0.5 g,0.0024 mol), 2,2,2-trichloroethyl(4-(dimethylcarbamoyl)phenyl)carbamate(0.978 g, 0.00288 mol; from Preparation 5), TEA (1.01 mL, 0.0072 mol)and toluene (20 mL) were added. The reaction mixture was maintained at105° C. for 12 h. The cooled reaction mixture was diluted with ethylacetate and washed with water. The ethyl acetate layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure to getthe crude product. The crude was purified by column chromatography using3% MeOH in chloroform to get the title compound [0.35 g, 36%]. ¹H NMR(300 MHz, DMSO-d₆): δ 9.30 (s, 1H), 8.96 (s, 1H), 8.0-7.92 (m, 1H),7.52-7.42 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s,6H); LC-MS (ESI): Calculated mass: 397.0; Observed mass: 400.0 (RT: 1.49min).

Step 3:4-(3-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,(3-(4-bromo-2,3-difluorophenyl)ureido)-N,N-dimethyl-benzamide (0.35 g,0.00088 mol) and 1,4-dioxane (15 mL) were added. To the flask,bis(pinacolato)diboron (0.335 g, 0.00132 mol), Pd(dppf)Cl₂.DCM (0.05 g,0.000062 mol) and KOAc (0.216 g, 0.0022 mol) was added. The reactionmixture was degassed with nitrogen for 5 min and maintained at 100° C.for 12 h. The reaction mass was cooled to room temperature and dilutedwith ethyl acetate. The ethyl acetate layer was washed with water, brineand dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure to obtain the crude product. The crude productwas subjected to column chromatography (60-120 silica gel, 5% MeOH inchloroform) to get the title compound [0.22 g, 56%]. ¹H NMR (300 MHz,CDCl₃): δ 9.36 (s, 1H), 8.96 (s, 1H), 8.10-8.02 (m, 1H), 7.52 (d, J=8.1Hz, 2H), 7.39 (d, J=7.5 Hz, 2H), 7.20-7.06 (m, 1H), 2.96 (s, 6H), 1.29(s, 12H). LC-MS (ESI): Calculated mass: 445.2; Observed mass: 446.4 (RT:1.12 min).

Example 1N,N-Dimethyl-4-(3-{4-[4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide

Step 1: N-(3-Bromo-phenyl)-2-hydroxyimino-acetamide

To a 3000 mL round bottom flask, 3-bromoaniline (50 g, 0.2907 mol),water (1500 mL), chloral hydrate (57.7 g, 0.3488 mol), hydroxylaminehydrochloride (64.6 g, 0.9302 mol) and sodium sulfate (250 g) wereadded. To this reaction mixture conc. HCl (76 mL) was slowly added. Thereaction mixture was stirred at 90° C. for 2 h. The white precipitatewas formed and was collected by filtration. The white solid was dried toget the title compound [60 g, 85%]. ¹H NMR (300 MHz, DMSO-d₆): δ 12.28(s, 1H), 10.38 (s, 1H), 8.03 (t, J=1.5 Hz, 1H), 7.62-7.65 (m, 2H),7.29-7.31 (m, 2H). LC-MS (ESI): Calculated mass: 242.0; Observed mass:243.0 [M+H]⁺ (RT: 0.17 min).

Step 2: 6-Bromo-1H-indole-2,3-dione

To the concentrated sulfuric acid (275 mL) at 50° C. was addedN-(3-Bromo-phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272 mol). Thetemperature was raised to 90° C. and maintained for 3 h. The reactionmixture was added to ice cold water to get yellow precipitate. Theprecipitate was filtered and dried to get the title compound as a yellowsolid [50 g, 98%]. This material was taken to the next step without anyfurther purification.

Step 3: 2-Amino-4-bromo-benzoic acid

To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione (50 g,0.2192 mol) and NaOH (20 g in 250 mL water) were added and cooled thereaction vessel to 0° C. To this reaction mixture 30% hydrogen peroxide(50 mL) was slowly added. The reaction mixture was stirred at 0° C. for2 h. Subsequently, the reaction mixture was acidified with 2N HCl [pH-6]at 0° C. to afford the solid compound. The solid material was collectedby filtration and dried to obtain the title compound [10 g, 21%]. ¹H NMR(300 MHz, DMSO-d₆): δ 7.59 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H),6.65 (dd, J′=8.7 Hz, J″=1.8 Hz, 1H) LC-MS (ESI): Calculated mass: 215.0;Observed mass: 215.9 [M+H]⁺ (RT: 0.83 min).

Step 4: 7-Bromo-1H-quinazoline-2,4-dione

To a 250 mL round bottom flask, 2-amino-4-bromo-benzoic acid (10 g,0.0463 mol) and urea (27.78 g, 0.4629 mol) were added. The reactionmixture was stirred at 195° C. for 3 h. The reaction mixture was allowedto reach 80° C. and water was added. The aqueous reaction mixture wasstirred at 80° C. for 5-10 min then allowed to reach room temperature.The solid was filtered, dried and azeotroped with toluene to afford thetitle compound [10 g, 90%]. This material was taken to the next stepwithout any further purification.

Step 5: 7-Bromo-2,4-dichloro-quinazoline

To a 250 mL round bottom flask, 7-bromo-1H-quinazoline-2,4-dione (10 g0.0413 mol) was charged. To the same flask POCl₃ (100 mL) and DIPEA (6.5mL, 0.0413 mol) were added. The reaction mixture was maintained at 130°C. for 12 h. The volatiles were evaporated and azeotroped with tolueneto get the crude residue. The crude residue was purified using, columnchromatography (60-120 silica gel, 10% ethyl acetate in hexane) to getthe title compound (7 g, 60%). ¹H NMR (300 MHz, CDCl₃): δ 8.41 (s, 1H),8.00-8.09 (m, 1H), 7.89-7.91 (m, 1H): LC-MS (ESI): Calculated mass:275.9; Observed mass: 276.8 [M+H]³⁰ (RT: 0.68 min).

Step 6: 7-Bromo-2-chloro-4-morpholin-4-yl-quinazoline

To an ice cold solution of 7-bromo-2,4-dichloro-quinazoline (7 g, 0.0255mol) in DCM (150 mL), morpholine (4.43 mL, 0.0509 mol) was slowly addedand the reaction was continued at 0° C. for 30 min. The solvent wasevaporated to dryness to get the crude compound. The crude product waspurified, using column chromatography (60-120 silica gel, 30% ethylacetate in hexane) to get the title compound (7 g, 84%). ¹H NMR (300MHz, CDCl₃): δ 8.17 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.63 (d,J=8.1 Hz, 1H), 3.72-3.74 (m, 8H): LC-MS (ESI): Calculated mass: 327.0;Observed mass: 329.8 [M+H]⁺ (RT: 0.45 min).

Step 7: 2-Chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazoline

To a 50 mL round bottom flask,7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.2 g, 0.0006 mol),pyrimidine-5-boronic acid (0.068 g, 0.0005 mol), sodium carbonate (0.129g, 0.0012 mol), DMF (10 mL) and water (3 mL) were added and degassed thereaction vessel with N₂ for 5-10 min. To the same reaction mixture,Pd(PPh₃)₂Cl₂ (0.029 g, 0.00004 mol) was added and again degassed with N₂for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. Thereaction mixture was cooled and diluted with ethyl acetate. The organiclayer was washed with water, brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure to afford the crude product.The crude product was purified; using column chromatography (60-120silica gel, 60% ethyl acetate in hexane) to yield the desired product[150 mg, 75%]. ¹H NMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 9.04 (s, 2H),7.85-8.45 (m, 2H), 7.60-7.64 (m, 1H), 3.82-3.91 (m, 8H); LC-MS (ESI):Calculated mass: 327.09; Observed mass: 328.0 [M+H]⁺ (RT: 0.98 min).

Step 8:N,N-Dimethyl-4-(3-{4-[4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide

To a 50 mL round bottom flask,2-chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazoline (150 mg, 0.00046mol),N,N-Dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(168 mg, 0.00041 mol), cesium carbonate (300 mg, 0.00092 mol), DMF (10mL) and water (3 mL) were added. The reaction mixture was degassed withN₂ for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (16 mg,0.000023 mol) was added and again degassed with N₂ for 5-10 min. Thereaction mixture was stirred at 95° C. for 2 h. The reaction mixture wascooled and diluted with ethyl acetate. The organic layer was washed withwater, brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to afford the crude product. The crude productwas purified using column chromatography (60-120 silica gel, 4% MeOH inchloroform) followed by preparative TLC (10% MeOH in chloroform) toyield the title compound [30 mg, 11%]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.36(s, 2H), 9.29 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.46 (d, J=8.8 Hz,2H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.93 (dd, J′=8.4Hz, J″=1.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.38(d, J=8.4 Hz, 2H), 3.87 (s, 8H), 2.96 (s, 6H); LC-MS (ESI): Calculatedmass: 574.2; Observed mass: 575.1 [M+H]⁺ (RT: 0.26 min).

Example 2N,N-Dimethyl-4-(3-{4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide

Step 1: 2-Chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline

To a 50 mL round bottom flask,7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (2 g, 0.0061 mol),5-methyl-2-furanboronic acid pinacol ester (1.1 g, 0.0091 mol), sodiumcarbonate (0.969 g, 0.0092 mol), DMF (80 mL) and water (20 mL) wereadded and degassed the reaction vessel with nitrogen for 5-10 min. Tothe same reaction mixture, Pd(PPh₃)₂Cl₂ (0.213 g, 0.0003 mol) was addedand again degassed with nitrogen for 5-10 min. The reaction mixture wasstirred at 95° C. for 2 h. The reaction mixture was cooled and dilutedwith ethyl acetate. The organic layer was washed with water, brine anddried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude product. The crude product was purified;using column chromatography (60-120 silica gel, 0-20% ethyl acetate inhexane) to yield the desired product [1.4 g, 70%]. ¹H NMR: (400 MHz,CDCl₃): δ 8.01 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (dd,J′=8.8 Hz, J″=1.6 Hz, 1H), 6.78 (d, J=3.2, 1H), 6.14-6.45 (m, 1H), 3.88(m, 8H), 2.42 (s, 3H); LC-MS (ESI): Calculated mass: 329.1; Observedmass: 330.0 [M+H]⁺ (RT: 1.71 min).

Step 2:N,N-Dimethyl-4-(3-{4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide

To a 50 mL round bottom flask,2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (1.4 g,0.0036 mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(2.25 g, 0.0055 mol), sodium carbonate (0.775 g, 0.0073 mol), toluene(12 mL), EtOH (12 mL) and water (12 mL) were added. The reaction mixturewas degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (128 mg, 0.000023 mol) was added and again degassed withnitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2h. The reaction mixture was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, brine and dried over sodiumsulfate. The solvent was removed under reduced pressure to afford thecrude product. The crude product was purified using columnchromatography (60-120 silica gel, 0-4% MeOH in chloroform) followed bypreparative HPLC (0.1% TFA in water and ACN) to yield the title compound[0.65 g, 27%]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.49 (brs, 1H), 9.27 (brs,1H), 8.30 (d, J=8.8 Hz, 2H), 8.11 (t, J=9.2 Hz, 2H), 7.85 (d, J=8.8 Hz,1H), 7.72 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8, 2H), 7.37 (d, J=8.4 Hz,2H), 7.22 (d, J=3.2 Hz, 1H), 6.37 (s, 1H), 4.22 (brs, 4H), 3.83 (brs,4H), 2.95 (s, 6H), 2.40 (s, 3H); LC-MS (ESI): Calculated mass: 576.2;Observed mass: 576.7 [M+H]⁺ (RT: 0.64 min).

A mixture ofN,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide(q eq.) and methanesulfonic acid (1 eq.) in acetone was maintained at65° C. for 3 h. The reaction mass was cooled to room temperature and thesolvent was evaporated under reduced pressure and azeotroped withtoluene [3 times]. The obtained solid was triturated with ethyl acetate,filtered and dried to obtain the methanesulfonic acid salt ofN,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamideas a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.43 (s, 1H), 9.18(s, 1H), 8.35 (d, J=8.7 Hz, 2H), 8.18 (d, J=8.1 Hz, 2H), 7.91 (d, J=9.3,1H), 7.88 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.7 Hz,2H), 7.30 (d, J=3.3, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.27 (s, 4H), 3.84 (s,4H), 2.96 (s, 6H), 2.44 (s, 3H), 2.34 (s, 3H); LC-MS (ESI): Calculatedmass: 576.2 (free base mass); Observed mass: 577.4 (RT=0.41 min)

A mixture ofN,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide(1 eq.) and trifluoroacetic acid (1 eq.) in acetone was maintained at65° C. for 3 h. The reaction mass was cooled to room temperature and thesolvent was evaporated under reduced pressure azeotroped with toluene [3times]. The obtained solid was triturated with ethyl acetate, filteredand dried to obtain the trifluoroacetic acid salt ofN,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamideas a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 9.31(s, 1H), 8.36 (d, J=8.8 Hz, 2H), 8.14 (t, J=4 Hz, 2H), 7.88 (d, J=8.4Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.27 (d, J=3.2 Hz, 1H), 6.38 (d, J=2.8 Hz, 1H), 4.22 (brs, 4H),3.84 (s, 4H), 2.97 (s, 6H), 2.43 (s, 3H). LC-MS (ESI): Calculated mass:576.2 (free base mass); Observed mass: 577.2 (RT=0.46 min)

Example 34-(3-{5-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-dimethyl-benzamide

Step 1:2-Chloro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazoline

To a 50 mL round bottom flask,7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.65 g, 0.0019 mol),3-methylsulfonylphenylboronic acid (0.35 g, 0.0018 mol), sodiumcarbonate (0.314 g, 0.0029 mol), DMF (25 mL) and water (6 mL) were addedand degassed the reaction vessel with nitrogen for 5-10 min. To the samereaction mixture, Pd(PPh₃)₂Cl₂ (0.069 g, 0.00099 mol) was added andagain degassed with nitrogen for 5-10 min. The reaction mixture wasstirred at 95° C. for 2 h. The reaction mixture was cooled and dilutedwith ethyl acetate. The organic layer was washed with water, brine anddried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude product. The crude product was purified;using column chromatography (60-120 silica gel, 50% ethyl acetate inhexane) to yield the desired product [400 mg, 80%]. LC-MS (ESI):Calculated mass: 403.1; Observed mass: 404.0 [M+H]⁺ (RT: 1.36 min).

Step 2:5-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-ylamine

To a 50 mL round bottom flask,2-chloro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazoline (0.15g, 0.00037 mol), 2-aminopyridine-5-boronic acid pinacol ester (0.122 g,0.0005568 mol), cesium carbonate (0.243 g, 0.00074 mol), DMF (4 mL) andwater (2 mL) were added. The reaction mixture was degassed with nitrogenfor 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (0.013 g,0.000018 mol) was added and again degassed with nitrogen for 5-10 min.The reaction mixture was stirred at 95° C. for 2 h. The reaction mixturewas cooled and diluted with ethyl acetate. The organic layer was washedwith water, brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to afford the crude product. The crude productwas purified using column chromatography (60-120 silica gel, 5% MeOH inchloroform) to yield the title compound (125 mg, 74%). LC-MS (ESI):Calculated mass: 461.2; Observed mass: 462.1 [M+H]⁺ (RT: 0.17 min).

Step 3:{5-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridine-2-yl}-carbamicacid 2,2,2-trichloroethyl ester

To a cooled solution (0° C.) of5-[7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-ylamine(125 mg, 0.000271 mmol) in DCM (4 mL) was added2,2,2-trichloroethylchloroformate (0.054 mL, 0.0004 mol) and TEA (0.056mL, 0.0004 mol). The reaction mixture was allowed to stir at ambienttemperature for 5 h. The volatiles were evaporated to get the crudeproduct (100 mg). This material was taken to the next step withoutfurther purification.

Step 4:4-(3-{5-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-dimethyl-benzamide

To a sealed tube,{5-[7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridine-2-yl}-carbamicacid 2,2,2-trichloroethyl ester (100 mg, 0.000312 mol),4-amino-N,N-dimethyl-benzamide (258 mg, 0.00156 mol), TEA (0.218 mL,0.00156 mol) and toluene (4 mL) were added, The reaction mixture washeated to 120° C. and maintained for 8 h. The reaction mixture wascooled and diluted with ethyl acetate. The organic layer was washed withwater, brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to afford the crude product. The crude productwas purified using column chromatography (60-120 silica gel, 0-3% MeOHand chloroform) to yield the desired product (15 mg, 15%). ¹H NMR (300MHz, DMSO-d₆): δ 11.69 (brs, 1H), 9.52 (brs, 1H) 9.07 (brs, 1H), 8.89(d, J=8.7 Hz, 1H), 8.40 (s, 1H), 8.24 (m, 3H), 8.07 (d, J=10.0 Hz, 1H),7.83-7.91 (m, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.40-7.45 (m, 3H), 3.91-3.96(m, 8H), 3.27 (s, 3H), 3.04 (s, 6H); LC-MS (ESI): Calculated mass:651.2; Observed mass: 652.2 (RT: 0.71 min).

Example 41-[4(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea

Step 1: N-(3-Bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide

To a 500 mL round bottom flask, 3-bromo-4-fluoraniline (5 g, 0.0261mol), water (300 mL), chloral hydrate (5.19 g, 0.0314 mol),hydroxylamine hydrochloride (5.8 g, 0.0835 mol) and sodium sulfate (25g) were added. To this reaction mixture, conc. HCl (7.5 mL) was slowlyadded. The reaction mixture was stirred at 90° C. for 3 h. Theprecipitate was formed and was collected by filtration. The solid wasdried to get the title compound (4.2 g, 61%). ¹H NMR (300 MHz, DMSO-d₆):δ 12.28 (s, 1H), 10.51 (s, 1H), 8.12 (dd, J=2.4 Hz, J=2.7 Hz, 1H), 7.68(m, 2H), 7.36 (t, J=8.7 Hz, 1H); LC-MS (ESI): Calculated mass: 260.0;Observed mass: 259.0 [M−H]⁺ (RT: 0.88 min).

Step 2: 6-Bromo-5-fluoro-1H-indole-2,3-dione

To the concentrated sulfuric acid (40 mL) at 50° C. was addedN-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide (4 g, 0.0152 mol).The temperature was raised to 90° C. and maintained for 3 h. Thereaction mixture was added to ice cold water to get the precipitate. Theprecipitate was filtered and dried to get the title compound (3.0 g,80%). LC-MS (ESI): Calculated mass: 243.0; Observed mass: 242.1 [M−H]⁺(RT: 0.47 min).

Step 3: 2-Amino-4-bromo-5-fluoro-benzoic acid

To a 100 mL round bottom flask, 6-bromo-5-fluoro-1H-indole-2,3-dione (3g, 0.0121 mol) and 2N NaOH (15 mL) were added and cooled the reactionvessel to 0° C. To this reaction mixture 30% hydrogen peroxide (10.5 mL)was slowly added. The reaction mixture was stirred at 0° C. for 3 h.Subsequently, the reaction mixture was acidified with 2 N HCl at 0° C.[pH-5] to afford the solid compound. The solid material was collected byfiltration and dried to obtain the title compound (700 mg, 25%). ¹H NMR(300 MHz, DMSO-d₆): δ 7.52 (d, J=9.6 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H);LC-MS (ESI): Calculated mass: 232.9; Observed mass: 231.9 [M−H]⁺ (RT:0.23 min).

Step 4: 7-Bromo-6-fluoro-1H-quinazoline-2,4-dione

To a 100 mL round bottom flask, 2-amino-4-bromo-5-fluoro-benzoic acid(0.7 g, 0.003 mol) and urea (1.07 g, 0.0018 mol) were added. Thereaction mixture was stirred at 200° C. for 2 h. The reaction mixturewas allowed to reach 100° C. and water was added. The aqueous reactionmixture was refluxed for 5-10 min, cooled to room temperature, to getthe precipitate. The solid was filtered and dried to afford the titlecompound (400 mg, 51%). This material was taken for next step withoutany further purification.

Step 5: 7-Bromo-2,4-dichloro-6-fluoro-quinazoline

To a 100 mL round bottom flask was charged with7-bromo-6-fluoro-1H-quinazoline-2,4-dione (0.4 g, 0.001532 mol). To thesame flask POCl₃ (15 mL) and DIPEA (0.714 mL, 0.005 mol) were added. Thereaction mixture was maintained at 140° C. for overnight. The volatileswere evaporated and azeotroped with toluene to get the residue. Thecrude residue was purified using column chromatography (60-120 silicagel, 20% ethyl acetate in hexane) to get the title compound (350 mg,77%). This material was immediately taken to the next step.

Step 6: 7-Bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline

To an ice cold solution of 7-bromo-2,4-dichloro-6-fluoro-quinazoline(0.35 g, 0.001178 mol) in DCM (15 mL), morpholine (0.247 mL, 2.946 mol)was slowly added and the reaction was continued for 20 min. The reactionmixture was diluted with DCM and washed with water. The organic layerwas dried over sodium sulfate and evaporated to get the crude. The crudewas purified using column chromatography (60-120 silica gel, 30% ethylacetate in hexane) to get the title compound (220 mg, 57%). ¹H NMR (300MHz, DMSO-d₆): δ 8.16 (d, J=6.6 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H),3.83-3.86 (m, 4H), 3.76-3.73 (m, 4H); LC-MS (ESI): Calculated mass:344.9; Observed mass: 347.8 [M+H]⁺ (RT: 1.70 min).

Step 7: 2-Chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline

To a 50 mL round bottom flask,7-bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline (200 mg,0.0005764 mol), pyridine-3-boronic acid (63.3 mg, 0.0005188 mol), sodiumcarbonate (152.6 mg, 0.001441 mol), DMF (10 mL) and water (5 mL) wereadded and degassed the reaction vessel with nitrogen for 5-10 min. Tothe same reaction mixture, Pd(PPh₃)₂Cl₂ (20.1 mg, 0.0000288 mol) wasadded and again degassed with N₂ for 5-10 min. The reaction mixture wasstirred at 95° C. for 2 h. The reaction mixture was cooled and dilutedwith ethyl acetate. The organic layer was washed with water, brine anddried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude product. The crude product was purifiedusing column chromatography (60-120 silica gel, 2% MeOH in chloroform)to yield the desired product (180 mg, 91%). ¹H NMR (300 MHz, CD₃OD): δ8.27-8.30 (m, 1H), 8.21-8.25 (m, 1H), 8.15-8.18 (m, 1H), 7.91-7.92 (m,1H), 7.74-7.78 (m, 1H), 7.47-7.51 (m, 1H), 3.99-4.01 (m, 4H), 3.85-3.88(m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 344.9[M+H]⁺ (RT: 1.3 min).

Step 8:1-[4(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea

To a 50 mL round bottom flask,2-chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline (90 mg,0.000259 mol),1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea(144.7 mg, 0.0003114 mol), cesium carbonate (212.3 mg, 0.000647 mol),DMF (5 mL) and water (2.5 mL) were added. The reaction mixture wasdegassed with nitrogen for 5-10 min. To the same reaction flask,Pd(PPh₃)₂Cl₂ (9.07 mg, 0.0000131 mol) was added and again degassed withnitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2h. The reaction mixture was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, brine and dried over sodiumsulfate. The solvent was removed under reduced pressure to afford thecrude product. The crude product was purified using columnchromatography (60-120 silica gel, 5% MeOH in chloroform) to yield thetitle compound (15 mg, 6%) ¹H NMR (300 MHz, DMSO-d₆): δ 9.05 (s, 1H),9.0 (s, 1H), 8.93 (brs, 1H), 8.68-8.72 (m, 1H), 7.92-8.73 (m, 5H),7.52-7.64 (m, 5H), 7.35 (d, J=8.1 Hz, 2H), 3.85 (s, 8H), 3.46-3.57 (m,4H), 2.24-2.37 (m, 4H), 2.19 (s, 3H); LC-MS (ESI): Calculated mass:646.2; Observed mass: 647.2 (RT: 0.11 min).

Example 54-(3-{4-[8-(3-Hydroxy-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide

Step 1: N-(2-Bromo-phenyl)-2-hydroxyimino-acetamide

To a 1000 mL round bottom flask, 2-bromoaniline (15 g, 0.0872 mol),water (400 mL), chloral hydrate (17.05 g, 0.1046 mol), hydroxylaminehydrochloride (19.25 g, 0.279 mol) and sodium sulfate (57.81 g) wereadded. To this reaction mixture conc. HCl (21 mL) was slowly added. Thereaction mixture was stirred at 100° C. for 3 h. The white precipitatewas formed and was collected by filtration. The white solid was dried toget the title compound [7 g, 33%]. ¹HNMR (300 MHz, DMSO-d₆): δ 12.46 (s,1H), 9.48 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.66(s, 1H), 7.42 (t, J=6.9 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H); LC-MS (ESI):Calculated mass: 241.9; Observed mass: 243.0 [M+H]⁺ (RT: 0.66 min).

Step 2: 8-Bromo-1H-indole-2,3-dione

To the concentrated sulfuric acid (70 mL) at 60° C. was addedN-(2-bromo-phenyl)-2-hydroxyimino-acetamide (7 g, 0.028 mol). Thetemperature was raised to 90° C. and maintained for 3 h. The reactionmixture was added to ice cold water to get yellow precipitate. Theprecipitate was filtered and dried to get the title compound as a yellowsolid [6.0 g, 92%]. ¹H NMR (300 MHz, DMSO-d₆): δ 11.33 (s, 1H), 7.79 (d,J=8.1 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H); LC-MS(ESI): Calculated mass: 224.9; Observed mass: 226.0 [M+H]⁺ (RT: 0.39min).

Step 3: 2-Amino-3-bromo-benzoic acid

To a 100 mL round bottom flask, 8-bromo-1H-indole-2,3-dione (6 g, 0.0234mol) and 2N NaOH (66.8 mL) were added and the reaction vessel cooled to0° C. To this reaction mixture 30% hydrogen peroxide (6 mL) was slowlyadded. The reaction mixture was stirred at 0° C. for 3 h. Subsequently,the reaction mixture was acidified with 2N HCl at 0° C. [pH-6] to affordthe solid compound. The solid material was collected by filtration anddried to obtain the title compound [5 g, 88%]. ¹H NMR (300 MHz,DMSO-d₆): δ 13.01 (brs, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.5 Hz,1H), 6.75 (brs, 2H), 6.52 (t, J=8.1 Hz, 1H); LC-MS (ESI): Calculatedmass: 214.9; Observed mass: 215.9 [M+H]⁺ (RT: 0.88 min).

Step 4: 8-Bromo-1H-quinazoline-2,4-dione

To a 100 mL round bottom flask, 2-amino-3-bromo-benzoic acid (5 g,0.0234 mol) and urea (7.33 g, 0.122 mol) were added. The reactionmixture was stirred at 195° C. for 3 h. The reaction mixture was allowedto reach 80° C. and water was added. The aqueous reaction mixture wasstirred for 5-10 min and filtered to afford the title compound [5.4 g,97%]. This material was taken to the next step without any furtherpurification.

Step 5: 8-Bromo-2,4-dichloro-quinazoline

A 100 mL round bottom flask was charged with8-bromo-1H-quinazoline-2,4-dione (5.4 g, 0.0224 mol). To the same flaskPOCl₃ (80 mL) and DIPEA (8 mL) were added. The reaction mixture wasmaintained at 130° C. for 12 h. The volatiles were evaporated andazeotroped with toluene (3×20 mL). The crude residue was purified usingcolumn chromatography (60-120 silica gel, 10% ethyl acetate in hexane)to get the title compound [5.5 g, 89%]. ¹H NMR (300 MHz, CDCl₃): δ 8.53(dd, J′=7.8 Hz, J″=1.2 Hz, 1H), 8.33 (dd, J′=8.4 Hz, J″=0.9 Hz, 1H),7.81 (t, J=8.4 Hz, 1H); LC-MS (ESI): Calculated mass: 275.8; Observedmass: 277.0 [M+H]⁺ (RT: 1.67 min).

Step 6: 8-Bromo-2-chloro-4-morpholin-4-yl-quinazoline

To an ice cold solution of 8-bromo-2,4-dichloro-quinazoline (5.5 g,0.0197 mol) in DCM (100 mL), morpholine (3.77 mL, 0.0433 mol) was slowlyadded and the reaction was continued for 15 min. The solvent wasevaporated to dryness to get the crude compound. The crude product waspurified, using column chromatography (60-120 silica gel, 5-30% ethylacetate in hexane) to get the title compound [2.5 g, 39%]. ¹H NMR (400MHz, CDCl₃): δ 8.05 (dd, J′=7.8 Hz, J″=1.2 Hz, 1H), 7.81 (dd, J′=8.4 Hz,J″=0.9 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 3.89 (s, 8H); LC-MS (ESI):Calculated mass: 326.9; Observed mass: 327.9 [M+H]⁺ (RT: 1.57 min).

Step 7: 3-(2-Chloro-4-morpholin-4-ylquinazolin-8-yl)-phenol

To a 50 mL round bottom flask,8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol),3-hydroxyphenylboronic acid (57 mg, 0.00041 mol), sodium carbonate (97mg, 0.00091 mol), DMF (10 mL) and water (5 mL) were added. The reactionmixture was degassed with nitrogen for 5-10 min. To the same flaskPd(PPh₃)₂Cl₂ (16 mg, 0.000022 mol) was added and again degassed withnitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2h. The reaction mixture was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, brine and dried over sodiumsulfate. The solvent was removed under reduced pressure to afford thecrude residue. The crude product was purified using columnchromatography (60-120 silica gel, 1% MeOH in chloroform) to yield thedesired title product (85 mg, 46%). ¹H NMR: (300 MHz, CDCl₃): δ7.70-7.78 (m, 2H), 7.40-7.44 (m, 1H), 7.20-7.26 (m, 1H), 7.03-7.05 (m,2H), 6.78-6.83 (m, 1H), 3.81-3.83 (m, 8H); LC-MS (ESI): Calculated mass:341.1; Observed mass: 342.1 [M+H]⁺ (RT: 1.53 min).

Step 8:4-(3-{4-[8-(3-Hydroxy-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,3-(2-chloro-4-morpholin-4-ylquinazolin-8-yl)-phenol (80 mg, 0.000234mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(114 mg, 0.00028 mol), cesium carbonate (153 mg, 0.00047 mol), DMF (7mL) and water (1 mL) were added. The reaction mixture was degassed withnitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (8 mg,0.0000011 mol) was added and again degassed with nitrogen for 5-10 min.The reaction mixture was stirred at 95° C. for 2 h. The reaction mixturewas cooled and diluted with ethyl acetate. The organic layer was washedwith water, brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to afford the crude product. The crude productwas purified using column chromatography (60-120 silica gel, 2-5% MeOHin chloroform) to yield the title compound [15 mg, 6%]. ¹H NMR: (300MHz, DMSO-d₆): δ 9.49 (s, 1H), 9.00 (s, 1H), 8.97 (s, 1H), 8.31 (d,J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.50-7.59(m, 5H), 7.29-7.35 (m, 3H), 7.16-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H),3.83 (m, 8H), 2.97 (s, 6H); LC-MS (ESI): Calculated mass: 588.2;Observed mass: 588.8 [M+H]⁺ (RT: 0.64 min).

Example 64-(3-{4-[8-(6-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide

Step 1: 2-Chloro-8-(6-fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazoline

To a 50 mL round bottom flask,8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol),2-fluoropyridine-5-boronic acid (58 mg, 0.00041 mol), sodium carbonate(72 mg, 0.00068 mol), DMF (10 mL) and water (3 mL) were added and thereaction vessel was degassed with nitrogen for 5-10 min. To the samereaction mixture, PdCl₂(PPh₃)₂ (16 mg, 0.000023 mol) was added and againdegassed with nitrogen for 5-10 min. The reaction mixture was stirred at95° C. for 2 h. The reaction mixture was cooled and diluted with ethylacetate. The organic layer was washed with water, brine and dried oversodium sulfate. The solvent was removed under reduced pressure to affordthe crude product. The crude product was purified using columnchromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yieldthe desired product [90 mg, 60%]. ¹H NMR (300 MHz, CDCl₃): δ 8.44 (s,1H), 8.17-8.24 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H),7.53 (t, J=7.5 Hz, 1H), 7.75 (dd, J′=2.7, J″=3.0 Hz, 1H), 3.89 (s, 8H).LC-MS (ESI): Calculated mass: 344.1; Observed mass: 345.0 [M+H]⁺ (RT:1.63 min).

Step 2:4-(3-{4-[8-(6-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,2-chloro-8-(6-fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazoline (70 mg,0.000203 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido]-benzamide (100 mg, 0.0002436 mol),cesium carbonate (133 mg, 0.000406 mol), DMF (3.5 mL) and water (0.9 mL)were added. The reaction mixture was degassed with nitrogen for 5-10min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (7 mg, 0.0000101 mol) wasadded and again degassed with nitrogen for 5-10 min. The reactionmixture was stirred at 95° C. for 2 h. The reaction mixture was cooledand diluted with ethyl acetate. The organic layer was washed with water,brine and dried over sodium sulfate. The solvent was removed underreduced pressure to afford the crude product. The crude product waspurified using column chromatography (60-120 silica gel, 2% MeOH inchloroform) to yield the title compound as a light yellow solid [8 mg,7%]. ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.95 (s, 1H), 8.60 (s,1H), 8.43 (m, 1H), 8.28 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.95(d, J=7.2 Hz, 1H), 7.58 (m, 3H), 7.49 (m, 2H), 7.39 (m, 3H), 3.84 (s,8H), 2.95 (s, 6H); LC-MS (ESI): Calculated mass: 591.2; Observed mass:591.9 [M+H]⁺ (RT: 1.53 min).

Example 72-{4-[3-(4-Dimethycarbamoyl-phenyl)-Ureido]-phenyl}-4-morpholin-4-yl-quinazoline-7-carboxylicacid (2-dimethylamino-ethyl)-amide

Step 1: 2,4-Dioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acidmethyl ester

To a 250 mL round bottom flask, 2-amino dimethyl terephthalate (3 g,0.0143 mol) and urea (4.3 g, 0.0717 mol) were added. The reactionmixture was stirred at 200° C. for 3 h. The reaction mixture was allowedto reach 100° C. and water was added. The aqueous reaction mixture wasstirred at 100° C. for 5-10 min then allowed to reach room temperature.The solid was filtered, washed with chloroform dried and azeotroped withtoluene to afford the title compound [2.5 g, 80%]. This material wastaken to the next step without any further purification. ¹H NMR; (400MHz, DMSO-d₆): δ 11.25 (brs, 2H), 7.98 (d, 1H, J=8.2 Hz), 7.78 (s, 1H),7.65 (d, J=8.2, 1.2 Hz, 1H), 3.98 (s, 3H): LC-MS (ESI): Calculated mass:220.0; Observed mass: 221.0 [M+H]⁺ (RT: 0.19 min).

Step 2: 2-Chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid methylester

To a 250 mL round bottom flask,7-methylcarboxylate-1H-quinazoline-2,4-dione (1.4 g 0.00636 mol) wasadded. To the same flask POCl₃ (20 mL) and N,N-dimethylaniline (0.62 g,0.00509 mol) were added. The reaction mixture was maintained at 120° C.for 5 h. The volatiles were evaporated and azeotroped with toluene toprovide the crude residue. The crude residue was titurated with DCM andfiltered through a Celite® pad. The filtrate was purified by columnchromatography (60-120 silica gel, 50% ethyl acetate in hexane) toprovide 7-methylcarboxylate-2,4-dichloro-quinazoline. To an ice coldsolution of 7-methylcarboxylate-2,4-dichloro-quinazoline (0.65 g 0.00253mol) in DCM (10 mL), morpholine (0.443 mL, 0.00507 mol) was slowly addedand the reaction was continued at 0° C. for 30 min. The solvent wasevaporated to dryness to get the crude compound. The crude product waspurified, using column chromatography (60-120 silica gel, 50% ethylacetate in hexane) to get the title compound (0.543 g, 70%). ¹H NMR;(400 MHz, DMSO-d₆): δ 8.20 (d, 1H, J=1.2 Hz), 7.98 (d, 1H, J=8.2 Hz),7.80 (dd, J=8.2, 1.2 Hz, 1H), 3.95 (s, 3H), 3.76-3.87 (m, 8H): LC-MS(ESI): Calculated mass: 307.0; Observed mass: 308.0 [M+H]⁺ (RT: 1.21min).

Step 3: 2-Chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid

To a 50 mL round bottom flask was added 7-methylcarboxylate-4-morpholine2-chloro-quinazoline (0.5 g, 0.00162 mol) and THF:MeOH:H₂O (1:1:1, 9mL). LiOH (0.273 g, 0.0065 mol) was then added and the reaction wasstirred at room temperature for 1 h. After completion of the reaction,solvent were removed under reduced pressure and acidified with HCl.During the acidification, a white solid was formed, which was collectedby filtration. The filter cake was washed with water (10 mL) and driedin a vacuum oven to give the title compound (0.38 g, 80%). ¹H NMR (400MHz, DMSO-d₆): δ 13.5 (brs, 1H), 8.20 (d, 1H, J=1.2 Hz), 7.98 (d, 1H,J=8.2 Hz), 7.80 (dd, J=8.2, 1.2 Hz, 1H), 3.76-3.87 (m, 8H): LC-MS (ESI):Calculated mass: 293.0; Observed mass: 294.0 [M+H]⁺ (RT: 0.44 min).

Step 4: 2-Chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid(2-dimethylamino-ethyl)-amide

To a 50 mL round bottom flask, 7-carboxylicacid-4-morpholine-2-chloro-quinazoline (0.3 g, 0.00102 mol) in DMF (5mL), N,N-dimethylethylene diamine (0.134 mL, 0.0012 mol), HATU (0.58 g,0.0015 mol) and DIPEA (0.353 mL, 0.00204 mol) were added. The reactionmixture was stirred at room temperature for 12 h. The reaction mixturewas diluted with water and extracted with ethyl acetate (3×500 mL). Theorganic layer was washed with water, brine and dried over sodiumsulfate. The solvent was removed under reduced pressure and the crudeproduct was purified, using column chromatography (60-120 silica gel, 1%MeOH in chloroform) to get the title compound (0.263 g, 70%). ¹H NMR;(400 MHz, DMSO-d₆): δ 8.79 (brs, 1H), 8.12-8.16 (m, 2H), 7.90 (d, 1H,J=8.4 Hz), 3.77-3.87 (m, 8H), 3.44 (d, 2H, J=8.0 Hz), 2.50-2.56 (brs2H), 2.29 (s, 6H): LC-MS (ESI): Calculated mass: 363.1; Observed mass:364.0 [M+H]⁺ (RT: 0.09 min).

Step 5:2-{4-[3-(4-Dimethycarbamoyl-phenyl)-Ureido]-phenyl}-4-morpholin-4-yl-quinazoline-7-carboxylicacid (2-dimethylamino-ethyl)-amide

To a 50 mL round bottom flask,2-chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid(2-dimethylamino-ethyl)-amide (0.08 g, 0.00022 mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(0.108 g, 0.000264 mol), cesium carbonate (0.143 g, 0.00044 mol), DMF (4mL), water (1 mL) were added. The reaction mixture was degassed withnitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (8 mg,0.000011 mol) was added and again degassed with nitrogen for 5-10 min.The reaction mixture was stirred at 95° C. for 5 h. The reaction mixturewas cooled and diluted with ethyl acetate. The organic layer was washedwith water, brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to afford the crude product. The crude productwas purified using column chromatography (60-120 silica gel, 15-20% MeOHin chloroform) to yield the crude title compound in 50% yield, followedby preparative HPLC (0.1% TFA in water and ACN) to yield the titlecompound [0.013 g, 10%]. ¹H NMR; (400 MHz, DMSO-d₆): δ 9.65 (brs, 1H),9.55 (s, 1H), 9.17 (s, 1H), 8.45 (brs, 1H), 8.43 (d, 2H, J=8.8 Hz), 8.16(d, 1H, J=8.4 Hz), 7.96 (brs, 1H), 7.67 (d, 2H, J=8.0 Hz), 7.54 (d, 2H,J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 3.85-3.94 (m, 8H), 3.70 (d, 2H, J=5.2Hz), 3.43 (brs, 2H), 2.95 (s, 6H), 2.86 (s, 6H): LC-MS (ESI): Calculatedmass: 610.3; Observed mass: 611.1 [M+H]⁺ (RT: 0.08 min).

Example 84-(3-{2-Fluoro-4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}ureido)dimethyl-benzamide

To a 50 mL round bottom flask,2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.05 g,0.1519 mmol),4-{3-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-N,N-dimethyl-benzamide(0.097 g, 0.0002279 mol), cesium carbonate (0.099 g, 0.0003038 mol),toluene (4 mL), EtOH (4 mL) and water (2 mL) were added. The reactionmixture was degassed with nitrogen for 5-10 min. To the same reactionflask, Pd (PPh₃)₂Cl₂ (0.005 g, 0.0000076 mol) was added and againdegassed with nitrogen for 5-10 min. The reaction mixture was stirred at95° C. for 2 h. The reaction mixture was cooled and diluted with ethylacetate. The organic layer was washed with water, brine and dried oversodium sulfate. The solvent was removed under reduced pressure to affordthe crude product. The crude product was purified using columnchromatography (60-120 silica gel, 0-4% MeOH in chloroform) followed bypreparative HPLC using 10 mM ammonium acetate in water and ACN to yieldthe title compound [0.005 g, 6%]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.47 (s,1H), 8.92 (d, J=2.0, 1H), 8.23-8.39 (m, 3H), 8.02 (d, J=8.8 Hz, 2H),7.76 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.39 (d,J=8.4, 2H), 7.18 (d, J=3.2 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 3.84 (s,8H), 2.97 (s, 6H), 2.42 (s, 3H): LC-MS (ESI): Calculated mass: 594.2;Observed mass: 595.2 [M+H]⁺ (RT: 1.28 min).

Example 9N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]-pyrimidin-2-yl)-phenyl]ureido}-benzamide

Step 1: 3-Amino-5-bromo-pyridine-2-carboxylic acid amide

To a 100 mL round bottom flask, Raney Nickel (2.5 g) and EtOH (150 mL)were added. To the same flask was added5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The reactionmass was stirred under hydrogen afor 14 h at ambient temperature. Thecatalyst was removed by filtration. The clear filtrate was evaporated toprovide the crude product. The crude was subjected to columnchromatography (60-120 silica gel, 30% ethyl acetate in hexane) toprovide the title compound as a light yellow solid [1.1 g, 23%]. ¹H NMR(300 MHz, DMSO-d₆): δ 7.89 (brs, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.40 (brs,1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (brs, 2H): LC-MS (ESI): Calculatedmass: 215.0; Observed mass: 216.8 [M+H]⁺ (RT: 0.38 min).

Step 2: 3-Amino-5-bromo-pyridine-2-carboxylic acid

To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylicacid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution(0.98 g in 10 mL water, 0.0245 mol) was added. The reaction mixture wasstirred at reflux temperature for 5 h. The volatiles were evaporatedunder reduced pressure to get the residue. The residue was neutralizedto pH=7.0, using 2N HCl at 0° C. to obtain the precipitate. Theprecipitate was filtered and dried to get the title compound as lightyellow solid [1 g, 95%]. ¹H NMR (300 MHz, DMSO-d₆): δ 7.65 (d, J=2.1 Hz,1H), 7.20 (d, J=2.1 Hz, 1H), 7.01-7.16 (brs, 2H); LC-MS (ESI):Calculated mass: 215.9; Observed mass: 217.0 [M+H]⁺ (RT: 0.43 min).

Step 3: 7-Bromo-pyrido[3,2-d]pyrimidine-2,4-diol

To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylicacid (1 g, 0.0046 mol) and urea (2.768 g, 0.4629 mol) were added. Thereaction mixture was stirred at 200° C. for 2.5 h. The reaction mixturewas cooled, water was added and stirred to provide a precipitate. Theprecipitate was filtered and dried to provide the title compound [1 g,91%]. This material was taken to the next step without any furtherpurification.

Step 4: 7-Bromo-2,4-dichloro-pyrido[3,2-d]pyrimidine

To a 100 mL round bottom flask, 7-bromo-pyrido[2,3-d]pyrimidine-2,4-diol(1 g, 0.0041 mol) was added. To the same flask, POCl₃ (10 mL) and DIPEA(1 mL) were added. The reaction mixture was maintained at 130° C. for 10h. The volatiles were evaporated and azeotroped with toluene (2×10 mL).The obtained residue was treated with ethyl acetate and filtered througha Celite® pad. The filtrate was evaporated to get the crude titlecompound [0.9 g, 78% (crude yield)]. This material was taken to the nextstep without any further purification.

Step 5: 7-Bromo-2-chloro-4-morpholin-4-yl-pyrido[3,2-d]pyrimidine

To an ice cold solution of crude7-bromo-2,4-dichloro-pyrido[3,2-d]pyrimidine (2.85 g, 0.0102 mol) in DCM(25 mL) at 0° C. was added morpholine (1.8 g, 0.0204 mol). The reactionwas continued at 0° C. for 30 min. The volatiles were evaporated andsubjected to column chromatography (60-120 silica gel, 0-12% ethylacetate in hexane) to get the title compound as a light yellow solid[0.35 g, 26%]. ¹H NMR (300 MHz, DMSO-d₆): δ 8.68 (d, J=2.7 Hz, 1H), 8.19(d, J=2.4 Hz, 1H), 3.86-3.89 (m, 8H); LC-MS (ESI): Calculated mass:328.0; Observed mass: 330.8 [M+H]⁺ (RT: 1.50 min).

Step 6:2-Chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]pyrimidine

To a 50 mL round bottom flask,7-bromo-2-chloro-4-morpholin-4-yl-pyrido[3,2-d]pyrimidine (120 mg,0.0003647 mol), pyrimidine-5-boronic acid (40.4 mg, 0.0003282 mol),sodium carbonate (57.9 mg, 0.0005471 mol), DMF (5 mL) and water (3 mL)were added and the reaction vessel degassed with nitrogen for 5-10 min.To the same reaction mixture, Pd(PPh₃)₂Cl₂ (15 mg, 0.0003 mol) was addedand again degassed with nitrogen for 5-10 min. The reaction mixture wasstirred at 95° C. for 2 h. The reaction mixture was cooled and dilutedwith ethyl acetate. The organic layer was washed with water, brine anddried over sodium sulfate. The solvent was removed under reducedpressure to afford the crude product. The crude product was purifiedusing column chromatography (60-120 silica gel, 0-1.5% MeOH inchloroform) to yield the desired product [55 mg, 43%]. ¹H NMR (300 MHz,CDCl₃): δ 9.35 (s, 1H), 9.08 (s, 2H), 8.91 (d, J=2.1 Hz, 1H), 8.22 (d,J=2.7 Hz, 1H), 3.89-3.92 (m, 8H); LC-MS (ESI): Calculated mass: 328.1;Observed mass: 329.1 [M+H]⁺ (RT: 0.56 min).

Step 7:N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]ureido}-benzamide

To a 50 mL round bottom flask,2-chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]pyrimidine (50mg, 0.0001521 mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(93.4 mg, 0.0002282 mol), cesium carbonate (99.2 mg, 0.0003042 mol), DMF(5 mL) and water (2.5 mL) were added. The reaction mixture was degassedwith nitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂(5.4 mg, 0.0000076 mol) was added and again degassed with nitrogen for5-10 min. The reaction mixture was stirred at 90° C. for 2.5 h. Thereaction mixture was cooled and diluted with ethyl acetate. The organiclayer was washed with water, brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure to afford the crude product.The crude product was purified using column chromatography (60-120silica gel, 0-4% MeOH in chloroform) and preparative TLC (10% MeOH inchloroform) to afford pure compound (12 mg, 80%). This compound wassubjected to prep HPLC using 10 mol % ammonium acetate in water toafford the title compound as light yellow solid [5 mg, 6%]. ¹H NMR (300MHz, DMSO-d₆): δ 9.30 (s, 1H) 9.18 (s, 2H), 9.00 (s, 1H), 8.93 (s, 1H),8.44 (d, J=8.7 Hz, 2H), 8.22 (d, J=7.5 Hz, 1H), 7.95 (d, J=11.4 Hz, 1H),7.63 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 2H),3.86 (s, 8H), 2.97 (s, 6H); LC-MS (ESI): Calculated mass: 575.2;Observed mass: 576.2 [M+H]⁺ (RT: 0.28 min).

Example 105-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylicacid

Step 1: 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde

To a 50 mL round bottom flask,7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (Example 1; 1.0 g, 0.00304mol) and 5-formyl-2-furanylboronic acid (0.384 g, 0.00274 mol), sodiumcarbonate (0.806 g, 0.0076 mol), toluene (15 mL), EtOH (15 mL) and water(5 mL) were added. The reaction mixture was degassed with nitrogen for5-10 min. To the same reaction mixture, Pd(PPh₃)₂Cl₂ (0.105 g, 0.000152mol) was added and again degassed with nitrogen for 5-10 min. Thereaction mixture was stirred at 75° C. for 2.5 h. The reaction mixturewas cooled and diluted with ethyl acetate. The organic layer was washedwith water, brine and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to afford the crude product. Thecrude product was purified; using column chromatography (60-120 silicagel, 75% ethyl acetate in hexane) to yield the desired product [0.65 g,62%]. ¹H NMR (300 MHz, CDCl₃): δ 9.73 (s, 1H), 8.20 (s, 1H), 7.90 (s,2H), 7.38 (d, J=3.6 Hz, 1H), 7.06 (d, J=3.6 Hz, 1H), 3.91 (s, 4H), 3.90(s, 4H). LC-MS (ESI): Calculated mass: 343.0; Observed mass: 344.3 (RT:1.21 min).

Step 2: methyl5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carboxylate

To a 100 mL flask,5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.6 g,0.0017 mol) in MeOH (60 mL) was added and cooled to 0° C. To thereaction flask, manganese (IV) oxide (0.74 g, 0.0085 mol) and sodiumcyanide (0.429 g, 0.0085 mol) were added at 0° C. The reaction mixturewas stirred at 25° C. for 3 h. The reaction mixture was diluted withchloroform and filtered through a pad of Celite® reagent. The filtratewas washed with water, brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure to get the title compound as a solid[0.52 g, 79%]. ¹H NMR (300 MHz, CDCl₃): δ 8.18 (s, 1H), 7.87-7.86 (m,2H), 7.29 (d, J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 3.93 (s, 3H), 3.89(s, 8H). LC-MS (ESI): Calculated mass: 373.1; Observed mass: 374.1 (RT:1.57 min).

Step 3: methyl5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylate

To a 50 mL round bottom flask, methyl5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carboxylate (0.2 g,0.00053 mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(0.262 g, 0.00064 mol), cesium carbonate (0.43 g, 0.00133 mol), toluene(10 mL), EtOH (10 mL), and water (5 mL) were added. The reaction mixturewas degassed with nitrogen for 5-10 min. To the same reaction flask,Pd(PPh₃)₂Cl₂ (0.0186 g, 0.000026 mol) was added and again degassed withnitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3h. The reaction mixture was cooled, diluted with chloroform, washed withwater, brine and dried over anhydrous sodium sulfate. The organic layerwas evaporated under reduced pressure to afford the crude product. Thecrude product was purified using column chromatography using 60-120silica gel and 4% MeOH in chloroform followed by recrystallization withMeOH to yield the title compound [0.18 g, 54%]. ¹H NMR (300 MHz,DMSO-d₆): δ 9.01 (s, 1H), 8.94 (s, 1H), 8.44 (d, J=8.7 Hz, 2H), 8.22 (s,1H), 8.10 (d, J=9.0 Hz, 1H), 7.87 (dd, J′=8.7, J″=1.5 Hz, 1H), 7.62 (d,J=8.7 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.42 (s, 1H), 7.37 (d, J=8.4 Hz,2H), 7.31 (s, 1H), 3.86 (s, 3H), 3.83 (s, 8H), 2.94 (s, 6H). LC-MS(ESI): Calculated mass: 620.2; Observed mass: 621.1 (RT: 0.72 min).

Step 4:5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylicacid (See, Scheme 11)

To a 100 mL round bottom flask, methyl5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylate(0.1 g, 0.00016 mol) in MeOH (2 mL), THF (2 mL) and water (2 mL) wasadded. Subsequently, lithium hydroxide monohydrate (0.034 g, 0.0008 mol)was added and stirred at 25° C. for 12 h. The volatiles were evaporatedunder reduced pressure, the residue redissolved in water and acidifiedwith 2 N HCl to obtain a pH of 5.0. The volatiles were evaporated underreduced pressure and the residue was stirred with water and filtered.The obtained solid was washed with MeOH to yield the title compound[0.06 g, 61%]. ¹H NMR (300 MHz, DMSO-d₆): δ 12.12 (s, 1H), 8.57 (s, 1H),8.54 (s, 1H), 8.25 (s, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.97 (d, J=7.5 Hz,2H), 7.87 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz,2H), 7.28 (s, 2H), 7.04 (s, 1H), 3.85 (s, 8H), 2.98 (s, 6H). LC-MS(ESI): Calculated mass: 606.2; Observed mass: 607.2 (RT: 0.63 min).

Example 11N,N-dimethyl-4-(3-(4-(7-(5-(4-methylpiperazine-1-carbonyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide(See, Scheme 11)

To a 50 mL round bottom flask,5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylicacid (0.1 g, 0.00016 mol; Example 10) and N-methyl piperazine (0.024 g,0.00024 mol) in DMF (5 mL) was added. To the flask, HATU (0.153 g,0.0004 and TEA (0.067 mL, 0.00048 mol) were added. The reaction mass wasstirred at room temperature for 12 h. To the reaction mass, ice coldwater was added to provide the solid. The obtained solid was collectedby filtration. The crude product was purified by column chromatographyusing 60-120 silica gel and 5% MeOH in chloroform. The solid was washedwith MeOH and filtered to yield the desired product [0.01 g, 9%]. ¹H NMR(300 MHz, DMSO-d₆): δ 9.11 (s, 1H), 9.05 (s, 1H), 8.43 (d, J=8.4 Hz,2H), 8.14 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J=8.4Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.4Hz, 2H), 7.16 (d, J=3.3 Hz, 1H), 3.82-3.54 (m, 16H), 2.94 (s, 6H), 2.39(s, 3H). LC-MS (ESI): Calculated mass: 688.3; Observed mass: 689.3 (RT:0.10 min).

Example 124-(3-(4-(7-(5-cyanofuran-2-yl)-4-morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide(See, Scheme 11)

Step 1: 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbonitrile

To a 50 mL round bottom flask,5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.48 g,0.0014 mol; prepared in a similar method to that described in Example10) and THF (10 mL) were added. To the same flask, iodine (0.39 g,0.00154 mol) and 30% aqueous ammonia (9.6 mL) were added. The reactionmixture was stirred at 25° C. The light brown reaction mixture turnedyellow after 3 h. The reaction was quenched by adding ethyl acetate (100mL) and 10% aqueous sodium thiosulfate (40 mL) and stirred for 5 min.The organic layer was separated, washed with water, dried over anhydroussodium sulfate and evaporated under reduced pressure to get the crudeproduct. The crude product was purified using column chromatography(60-120 silica gel, 10-50% ethyl acetate in hexane) to yield the desiredproduct as a off white solid [0.31 g, 65%]. ¹H NMR (300 MHz, CDCl₃): δ8.11 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.24 (d,J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 3.95 (s, 8H). LC-MS (ESI):Calculated mass: 340.0; Observed mass: 341.0 (RT: 1.55 min).

Step 2:4-(3-(4-(7-(5-cyanofuran-2-yl)-4-morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbonitrile (0.12 g,0.00035 mol),4-(3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide(0.144 g, 0.00053 mol), cesium carbonate (0.228 g, 0.0007 mol), DMF (3mL) and water (3 mL) were added. The reaction mixture was degassed withnitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (0.013g, 0.0000175 mol) was added and again degassed with nitrogen for 5-10min. The reaction mixture was stirred at 95° C. for 2 h. To the cooledreaction mixture, water was added and extracted with ethyl acetate. Theorganic layer was separated, washed with water, brine and dried overanhydrous sodium sulfate. The organic layer was evaporated under reducedpressure to afford the crude product. The crude product was purified bycolumn chromatography using 60-120 silica gel and 2-5% MeOH inchloroform to obtain the title compound [0.013 g, 6%]. ¹H NMR (400 MHz,DMSO-d₆): δ 9.21 (s, 1H), 9.04 (s, 1H), 8.27 (d, J=2.0 Hz, 1H),8.19-8.13 (m, 2H), 7.93 (dd, J′=1.6, J″=8.4 Hz, 1H), 7.82 (d, J=4.0 Hz,1H), 7.64 (d, J=3.6 Hz, 2H), 7.61 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.4 Hz,2H), 7.28 (dd, J′=8.8 Hz, J″=2.0 Hz, 2H), 3.83 (s, 8H), 2.96 (s, 6H).LC-MS (ESI): Calculated mass: 605.2; Observed mass: 606.2 (RT: 1.17min).

Example 134-(3-(4-(7-(5-acetylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide(See, Scheme 11)

Step 1: 1-(5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-yl)ethanol

To a 50 mL round bottom flask,5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.5 g,0.001457 mol) and THF (25 mL) was added and cooled to 0° C. To the flaskwas slowly added 1.5 M methyl magnesium bromide in diethyl ether (0.145mL, 0.002186 mol). The resulting reaction mixture was stirred at roomtemperature for 3 h. The reaction was quenched with water and extractedwith ethyl acetate (3×50 mL). The organic layer was dried over anhydroussodium sulfate and evaporated to provide the crude product. The crudeproduct was purified by column chromatography using 60-120 silica geland 40% ethyl acetate in hexane [0.3 g, 57%]. ¹H NMR (300 MHz, CDCl₃): δ8.05 (d, J=1.2 Hz, 1H), 7.83 (d, J=6.3 Hz, 1H), 7.71 (dd, J′=6.6, J″=1.2Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.40 (d, J=2.7 Hz, 1H), 4.91 (q, J=4.8Hz, 1H), 3.89 (s, 8H), 1.63 (d, J=4.8 Hz, 3H). LC-MS (ESI): Calculatedmass: 359. 1; Observed mass: 360.1 (RT: 1.58 min).

Step 2: 1-(5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-yl)ethanone

To a 50 mL round bottom flask,(5-(2-chloro-4-morpholino-quinazolin-7-yl) furan-2-yl) EtOH (0.3 g,0.00084 mol) and DCM (50 mL) were added. To the flask, manganese (IV)oxide (0.36 g, 0.0042 mol) was added. The reaction mixture was stirredat room temperature for 12 h. The reaction mass was filtered through apad of Celite® reagent. The filtrate was evaporated to get the titlecompound [0.25 g, 84%]. ¹H NMR (300 MHz, CDCl₃): δ 8.20 (s, 1H), 7.91(d, J=8.7 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 6.99(d, J=3.6 Hz, 1H), 3.90 (s, 8H), 2.56 (s, 3H). LC-MS (ESI): Calculatedmass: 357.1; Observed mass: 358.1 (RT: 1.35 min).

Step 3:4-(3-(4-(7-(5-acetylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,1-(5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-yl)ethanone (0.1 g,0.00028 mol),2-fluoro-N,N-dimethyl-4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-benzamide(0.144 g, 0.00034 mol), cesium carbonate (0.228 g, 0.0007 mol), toluene(7 mL) and EtOH (7 mL), and water (3 mL) were added. The reactionmixture was degassed with nitrogen for 5-10 min. To the same reactionflask, Pd(PPh₃)₂Cl₂ (0.0098 g, 0.000014 mol) was added and againdegassed with nitrogen for 5-10 min. The reaction mixture was stirred at75° C. for 3 h. The reaction mixture was cooled, diluted withchloroform, washed with water, brine and dried over anhydrous sodiumsulfate. The organic layer was evaporated under reduced pressure toafford the crude product. The crude product was purified by columnchromatography using 60-120 silica gel and 4% MeOH in chloroform. Thecompound was further purified by prep HPLC using 10 mM ammonium acetatein water and ACN to obtain the title compound [0.01 g, 6%]. ¹H NMR (400MHz, DMSO-d₆): δ 9.04 (s, 1H), 8.96 (s, 1H), 8.46 (d, J=8.4 Hz, 2H),8.28 (s, 1H), 8.13 (d, 1H, J=8.8 Hz), 7.92 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.4 Hz, 3H), 7.55-7.52 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 3.85 (s, 8H),2.97 (s, 6H), 2.56 (s, 3H). LC-MS (ESI): Calculated mass: 622.2;Observed mass: 623.2 (RT: 0.45 min).

Example 144-(3-(2,3-difluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask,4-(2-chloro-7-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine(0.1 g, 0.0003 mol),4-(3-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide(0.16 g, 0.00036 mol), cesium carbonate (0.244 g, 0.00075 mol), toluene(7 mL), EtOH (7 mL), and water (3 mL) were added. The reaction mixturewas degassed with nitrogen for 5-10 min. To the same reaction flask,Pd(PPh₃)₂Cl₂ (0.0105 g, 0.000015 mol) was added and again degassed withnitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3h. To the cooled reaction mixture, ice cold water was added to obtainthe solid. The crude product was obtained by the filtration of thesolid. The crude product was purified by column chromatography using60-120 silica gel and 4% MeOH in chloroform to isolate the product. Theisolated product was washed with MeOH and filtered. The compound wasfurther purified by prep TLC using 7% MeOH in chloroform to yield thetitle compound [0.02 g, 11%]. ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (brs,1H), 9.09 (d, J=2.0 Hz, 1H), 9.01 (brs, 1H), 8.53 (s, 1H), 8.32 (d,J=2.0 Hz, 1H), 8.24 (s, 1H), 8.14-7.97 (m, 2H), 7.54 (d, J=8.4 Hz, 2H),7.40 (d, J=8.4 Hz, 2H), 4.49 (brs, 4H), 3.92 (s, 3H), 3.81 (brs, 1H),2.96 (s, 6H). LC-MS (ESI): Calculated mass: 613.2; Observed mass: 614.2(RT: 0.63 min).

Example 154-(3-(2-fluoro-4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide(See, Scheme 11)

Step 1:5-(2-chloro-4-morpholino-pyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde

To a 50 mL round bottom flask,4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.0 g,0.00303 mol; prepared as described in Scheme 7A) and5-formyl-2-furanylboronic acid (0.38 g, 0.00273 mol), sodium carbonate(0.64 g, 0.00606 mol) toluene (5 mL), EtOH (5 mL) and water (5 mL) wereadded. The reaction vessel was degassed with nitrogen for 5-10 min. Tothe same reaction mixture, Pd(PPh₃)₂Cl₂ (0.106 g, 0.0001515 mol) wasadded and again degassed with nitrogen for 5-10 min. The reactionmixture was stirred at 90° C. for 2 h. The reaction mixture was cooledand diluted with chloroform. The organic layer was washed with water,brine and dried over sodium sulfate. The solvent was removed under thereduced pressure to afford the crude product. The crude product waspurified using column chromatography (60-120 silica gel, chloroform) toyield the desired product as a yellow solid [0.48 g, 46%]. ¹H NMR (300MHz, CDCl₃): δ 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz,1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50 (brs, 4H),3.91-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass:345.0 (RT: 1.39 min).

Step 2:1-(5-(2-chloro-4-morpholino-pyrido[3,2-d]pyrimidin-7-yl)furan-2-yl)ethanol

To a 50 mL round bottom flask,5-(2-chloro-4-morpholino-pyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde(0.4 g, 0.0012 mol) and THF (15 mL) were added and cooled to 0-5° C. Tothe flask was slowly added 3.0 M methyl magnesium bromide in diethylether (0.6 mL, 0.0036 mol). The resulting reaction mixture was stirredat room temperature for 2 h. To the reaction mass, water was added andextracted with DCM. The organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced to get the crude product. The crudeproduct was purified by column chromatography using 1% MeOH inchloroform [0.17 g, 40%]. LC-MS (ESI): Calculated mass: 360.1; Observedmass: 361.1 (RT: 1.29 min).

Step 3:4-(3-(2-fluoro-4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

This compound was prepared by the method as described in Scheme 7B. ¹HNMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 9.12 (d, J=2 Hz, 1H), 8.89 (s,1H), 8.36-8.34 (m, 1H), 8.28-8.26 (m, 2H), 8.24 (d, J=12.8 Hz, 1H), 7.54(d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.36 (d, J=3.2 Hz, 1H), 6.50(d, J=3.2 Hz, 1H), 5.51 (d, J=5.2 Hz, 1H), 4.83-4.82 (m, 1H), 4.52 (brs,4H), 3.84 (brs, 4H), 2.97 (s, 6H), 1.48 (d, 3H, J=6.4 Hz); LC-MS (ESI):Calculated mass: 625.2; Observed mass: 626.2 (RT: 0.92 min).

Example 164-(3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide(See, Scheme 12)

Step 1: 2-(2-chloro-4-morpholino-quinazolin-7-yl)propan-2-ol

To a 25 mL round bottom flask, methyl2-chloro-4-morpholino-quinazoline-7-carboxylate (0.5 g, 0.001628 mol;prepared as described in Example 7; Scheme 8A) and anhydrous THF wereadded and cooled to 0° C. To the flask was added methyl magnesiumbromide (4.65 ml of 1.4 M in diethyl ether, 0.006514 mol) drop wise at0° C. and the reaction mixture was stirred at room temperature for 12 h.The reaction mass was diluted with ethyl acetate and washed with water.The ethyl acetate layer was dried over anhydrous sodium sulfate andevaporated under reduced to get the crude product. The crude product waspurified by column chromatography using 60-120 silica gel and 50% ethylacetate in hexane to yield the title compound [0.28 g, 56%]. ¹H NMR (300MHz, CDCl₃): δ 7.85 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.7 Hz 1H), 7.64 (dd,J′=2.1, J′″=8.7 Hz, 1H), 3.87 (s, 8H), 1.63 (s, 6H). LC-MS (ESI):Calculated mass: 307.78; Observed mass: 308.1 (RT: 0.42 min).

Step 2:4-(3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide

To a 50 mL round bottom flask, 2-(2-chloro-4-morpholino-quinazolin-7-yl)propan-2-ol (0.08 g, 0.00026 mol),N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide(0.128 g, 0.000312 mol), cesium carbonate (0.169 g, 0.00052 mol), DMF (3mL) and water (1 mL) were added. The reaction mixture was degassed withnitrogen for 5-10 min. To the same reaction flask, Pd(PPh₃)₂Cl₂ (0.009g, 0.000013 mol) was added and again degassed with nitrogen for 5-10min. The reaction mixture was stirred at 95° C. for 5 h. To the cooledreaction mixture, water was added and extracted with ethyl acetate. Theorganic layer was separated, washed with water, brine and dried overanhydrous sodium sulfate. The organic layer was evaporated under reducedpressure to afford the crude product. The crude product was purified bycolumn chromatography using 60-120 silica gel and 10% MeOH inchloroform. The compound was further purified by prep TLC using 10% MeOHin chloroform to obtain the title compound [0.007 g, 5%]. ¹H NMR (400MHz, DMSO-d₆): δ 9.02 (s, 1H), 8.97 (s, 1H), 8.44 (d, J=8.8 Hz, 2H),7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.8 Hz, 3H),7.54 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 3.83 (brs,4H), 3.81 (brs, 4H), 2.96 (s, 6H), 1.52 (s, 6H). LC-MS (ESI): Calculatedmass: 554.2; Observed mass: 555.1 (RT: 0.17 min).

Example 17N-(4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)phenyl)acetamide(See, Scheme 10)

To a 50 ml, round bottom flask,2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.15 g,0.00045 mol; prepared as described in Example 2; Scheme 6B),N-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)phenyl)acetamide(0.23 g, 0.00059 mol; prepared according to the methods described inScheme 9), cesium carbonate (0.44 g, 0.00135 mol), toluene (10 mL), EtOH(4 mL) and water (2 mL) were added. The reaction mixture was degassedwith nitrogen for 5-10 min. To the same reaction flask, Pd (PPh₃)₂Cl₂(0.022 g, 0.0000315 mol) was added and again degassed with nitrogen for5-10 min. The reaction mixture was stirred at 95° C. for 3 h. Thereaction mixture was cooled to room temperature to get the precipitate.The precipitate was collected by filtration to afford the crude product.The crude product was purified using column chromatography (60-120silica gel, 3% MeOH in chloroform). The compound was further purified byflash column chromatography using 230-400 silica gel and 1.5% MeOH inchloroform to yield the title compound [0.0252 g, 10%]. ¹H NMR (400 MHz,DMSO-d₆): δ 9.86 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.42 (d, J=8.8 Hz,2H), 8.01 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.8 Hz,2H), 7.51 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.17 (d, J=3.2 Hz,1H), 6.32 (d, J=2.8 Hz, 1H), 3.83 (s, 4H), 3.80 (s, 4H), 2.41 (s, 3H),2.02 (s, 3H). LC-MS (ESI): Calculated mass: 562.2; Observed mass: 563.1(RT: 0.64 min).

Example 181-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)-3-(4-(2-oxopyrrolidin-1-yl)phenyl)urea(See, Scheme 10)

To a 50 mL round bottom flask,2-Chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.12 g,0.00036 mol; prepared as described in Example 2; Scheme 6B),1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.184 g, 0.00043 mol; prepared according to the methods described inScheme 9), cesium carbonate (0.296 g, 0.0009 mol), toluene (7 mL), EtOH(7 mL) and water (3 mL) were added. The reaction mixture was degassedwith nitrogen for 5-10 min. To the same reaction flask, Pd (PPh₃)₂Cl₂(0.0128 g, 0.000018 mol) was added and again degassed with nitrogen for5-10 min. The reaction mixture was stirred at 95° C. for 3 h. Thereaction mixture was cooled and diluted with chloroform. The organiclayer was separated, washed with water, brine and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure to affordthe crude product. The crude product was purified by flash columnchromatography using 230-400 silica gel, 2% MeOH in chloroform. Thecompound was further purified by prep TLC using 4% MeOH in chloroform toyield the title compound [0.015 g, 7%]. ¹H NMR (300 MHz, DMSO-d₆): δ8.92 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=7.2 Hz, 2H), 8.02 (d, J=8.1 Hz,2H), 7.75 (d, J=8.4 Hz, 1H), 7.62 (t, J=8.7 Hz, 4H), 7.48 (d, J=9 Hz,2H), 7.17 (d, J=3.3 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 3.83 (m, 10H), 2.47(d, J=8.4 Hz, 2H), 2.41 (s, 3H), 2.08 (m, 2H); LC-MS (ESI): Calculatedmass: 588.2; Observed mass: 589.2 (RT: 0.13 min).

Examples 19-452

Additional compounds listed in Table 1 were prepared in a similarmanner, using the methods described for Examples 1 to 18 and in theSchemes 1 to 15. In some cases, compounds were isolated andcharacterized as the trifluoroacetate salt. LC-MS characterization datafor Examples 1 to 294 are tabulated in Table 2, below. Furtheradditional compounds of the invention, including those described inExamples 295-452, are prepared in a similar manner to the methodsdescribed for the Examples 1 to 18 and in Schemes 1 to 15.

TABLE 1 Synthetic Ex Structure Structure Name Scheme  1

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7- pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}- benzamide 6B  2

N,N-Dimethyl-4-(3-{4-[7- (5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)- benzamide 6B  3

4-(3-{5-[7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)- N,N-dimethyl-benzamide 6E  4

1-[4-(6-Fluoro-4- morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]- 3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea 6G  5

4-(3-{4-[8-(3-Hydroxy- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6F  6

4-(3-{4-[8-(6-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6F  7

2-{4-[3-(4- Dimethylcarbamoyl- phenyl)-ureido]-phenyl}-4-morpholin-4-yl-quinazoline- 7-carboxylic acid (2- dimethylamino-ethyl)-amide 8A  8

4-(3-{2-Fluoro-4-[7-(5- methyl-furan-2-yl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6D  9

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7- pyrimidin-5-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]- ureido}-benzamide 7A  10

5-(2-(4-(3-(4- (dimethylcarbamoyl)phenyl) ureido)phenyl)-4-morpholino-quinazolin-7- yl)furan-2-carboxylic acid 11 + 6B  11

N,N-dimethyl-4-(3-(4-(7-(5- (4-methylpiperazine-1-carbonyl)furan-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)ureido)-benzamide 11 + 6B  12

4-(3-(4-(7-(5-cyanofuran-2- yl)-4-morpholino- quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N- dimethyl-benzamide 11 + 6  13

4-(3-(4-(7-(5-acetylfuran-2- yl)-4-morpholino- quinazolin-2-yl)pehnyl)ureido)-2-fluoro- N,N-dimethyl-benzamide 11 + 6  14

4-(3-(2,3-difluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide 2 + 7  15

4-(3-(2-fluoro-4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide 11 + 7B  16

4-(3-(4-(7-(2- hydroxypropan-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 8A + 12  17

N-(4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-phenyl)- acetamide 10  18

1-(4-(7-(5-methylfuran-2- yl)-4-morpholino- quinazolin-2-yl)phenyl)-3-(4-(2-oxopyrrolidin-1- yl)phenyl)urea 10  19

4-(3-{4-(7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- diethyl-benzamide 6B  20

4-(3-{4-[7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N- methyl-benzamide 6B  21

4-(3-{4-[7-(2-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  22

N,N-Dimethyl-4-(3-{4-[7- (1-methyl-1H-pyrazol-4-yl)- 4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-benzamide 6B  23

4-(3-{4-[7-(3- Methanesulfonylamino- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  24

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]- ureido}-benzamide 6B  25

4-(3-{4-[7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)- benzamide 6B  26

1-{4-[7-(2-Fluoro-pyridin- 3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-3- [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea 6B  27

1-[4-(4-Methyl-piperazine- l-carbonyl)-phenyl]-3-{4-[7-(1-methyl-1H-pyrazol-4- yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- urea 6B  28

5-(3-{4-[7-(2-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-pyridine-2- carboxylic acid dimethylamide 6B  29

4-{3-[4-(6-Fluoro-4- morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]- ureido}-N,N-dimethyl- benzamide 6G  30

4-{3-[4-(6-Fluoro-4- morpholin-4-yl-7- pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N- dimethyl-benzamide 6G  31

5-(3-{4-[7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)- pyridine-2-carboxylic acid dimethylamide 6B  32

1-(4-(4-methylpiperazine-1- carbonyl)phenyl)-3-(4-(7-(3-(methylsulfonyl)phenyl)- 4-morpholino-quinazolin-2- yl)phenyl)urea 6B 33

1-[4-(4-Methyl-piperazine- 1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7- pyridin-3-yl-quinazolin-2- yl)-phenyl]-urea 6B  34

4-(3-{4-[7-(5- Methanesulfonyl-pyridin-3- yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  35

4-(3-{4-[6-Fluoro-7-(1- methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide6G  36

4-(3-{4-[6-Fluoro-7-(3- methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide6G  37

1-[4-(4-Methyl-piperazine- 1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7- thiophen-3-yl-quinazolin-2- yl)-phenyl]-urea 6B  38

4-(3-{4-[6-Fluoro-7-(5- methanesulfonyl-pyridin-3- yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6G  39

4-(3-{4-[7-(3- Methanesulfonyl-phenyl)-4- morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 7A  40

4-(3-{4-[8-(2-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6F  41

4-(3-{4-[7-(3-Hydroxy- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  42

N,N-Dimethyl-4-(3-{4-[7- (1-methyl-1H-pyrazol-4-yl)- 4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2- yl]-phenyl}-ureido)- benzamide 7A  43

N,N-Dimethyl-4-(3-{4-[7- (5-methyl-furan-2-yl)-4-morpholin-4-yl-pyrido[3,2- d]pyrimidin-2-yl]-phenyl}- ureido)-benzamide7A  44

N-(2-Dimethylamino- ethyl)-N-methyl-4-{3-[4-(4- morpholin-4-yl-7-pyrimidin-5-yl-quinazolin- 2-yl)-phenyl]-ureido}- benzamide 6B  45

4-(3-{4-[7-(3- Hydroxymethyl-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  46

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-pyridin-3-yl-pyrido[3,2-d]pyrimidin- 2-yl)-phenyl]-ureido}- benzamide 7A  47

4-(3-{4-[7-(3-Fluoro- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  48

4-(3-{4-[7-(3-Methoxy- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  49

4-(3-{4-[7-(3-Acetylamino- phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 6B  50

4-(3-{4-[7-(3- Dimethylamino-phenyl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  51

4-{3-[4-(7-Furan-2-yl-4- morpholin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N- dimethyl-benzamide 6B  52

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-thiophen-3-yl-quinazolin-2-yl)- phenyl]-ureido}-benzamide 6B  53

4-{3-[4-(7-Furan-3-yl-4- morpholin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N- dimethyl-benzamide 6B  54

4-(3-{5-[7-(2-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-N,N- dimethyl-benzamide 6E  55

N,N-Dimethyl-4-(3-{5-[7- (1-methyl-1H-pyrazol-4-yl)- 4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2- yl}-ureido)-benzamide 6E  56

N-Methyl-4-(3-{4-[7-(5- methyl-furan-2-yl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)- benzamide 6B  57

N,N-Dimethyl-4-(3-{5-[7- (5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-pyridin-2-yl}-ureido)- benzamide 6E  58

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-pyridin-4-yl-quinazolin-2-yl)-phenyl]- ureido}-benzamide 6B  59

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-quinolin-3-yl-quinazolin-2-yl)- phenyl]-ureido}-benzamide 6B  60

4-(3-{4-[7-(6-Methoxy- pyridin-3-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  61

N,N-Dimethyl-4-(3-{4-[7- (5-methyl-thiophen-2-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)- benzamide 6B  62

N,N-Dimethyl-4-(3-{4-[7- (4-methyl-pyridin-3-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)- benzamide 6B  63

N-(2-Dimethylamino- ethyl)-N-methyl-4-(3-{4-[7- (5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)- benzamide 6B  64

4-{3-[4-(7-Benzofuran-2-yl- 4-morpholin-4-yl- quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl- benzamide 6B  65

4-(3-{4-[7-(3-Fluoro- pyridin-4-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  66

4-(3-{4-[7-(5-Acetylamino- pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]- phenyl}-ureido)-N,N- dimethyl-benzamide 6B  67

1-[4-(4-Methyl-piperazine- 1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7- pyrimidin-5-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]- urea 7A  68

4-(3-{4-[7-(2-Fluoro- pyridin-4-yl)-4-morpholin- 4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  69

1-[4-(4-Methyl-piperazine- 1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7- pyridin-4-yl-quinazolin-2- yl)-phenyl]-urea 6B  70

1-{4-[7-(5-Methyl-furan-2- yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-3- [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea 6B  71

N,N-Dimethyl-4-(3-{4-[8- (5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin- 2-yl]-phenyl}-ureido)- benzamide 6F  72

N-(2-Dimethylamino- ethyl)-N-methyl-4-{3-[4-(4-morpholin-4-yl-7-pyridin-4- yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide 6B  73

1-[4-(4-Methyl-piperazine- l-carbonyl)-phenyl]-3-{4-[7-(1-methyl-1H-pyrazol-4- yl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2- yl]-phenyl}-urea 7A  74

N,N-Dimethyl-4-{3-[4-(4- morpholin-4-yl-7-thiophen-2-yl-quinazolin-2-yl)- phenyl]-ureido}-benzamide 6B  75

4-(3-{4-[7-(2-Methoxy- pyrimidin-5-yl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  76

4-(3-{4-[7-(2-Amino- pyrimidin-5-yl)-4- morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N- dimethyl-benzamide 6B  77

4-(3-(4-(7-(5-(2- (Dimethylamino)acetamido) pyridin-3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido]-N,N- dimethyl-benzamide 6B  78

4-(3-{4-[7-(2-Fluoro- pyridin-3-yl)-4-morpholin- 4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}- ureido)-N,N-dimethyl- benzamide 7A  79

1-[4-(4-Methyl-piperazine- 1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7- pyrimidin-5-yl-quinazolin- 2-yl)-phenyl]-urea 6B 80

N,N-Dimethyl-4-(3-{4-[7- (furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]- phenyl}-ureido)-benzamide 6B  81

1-(4-(4- (dimethylamino)piperidine- 1-carbonyl)phenyl)-3-(5-(7-(2-fluoropyridin-3-yl)-4- morpholino-quinazolin-2- yl)pyridin-2-yl)urea6E  82

4-(3-(2-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide 7B  83

4-(3-(4-(7-(1-(2- (dimethylamino)ethyl)-1H- pyrazol-4-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B  84

4-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D  85

N,N-dimethyl-4-(3-(5-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2-yl)pyridin-2- yl)ureido)-benzamide7 + 6E  86

N,N-dimethyl-4-(3-(4-(4- morpholino-7-(pyridazin-4- yl)quinazolin-2-yl)phenyl)ureido)- benzamide 6 + 6B  87

4-(3-(4-(6-fluoro-7-(5- methylfuran-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G  88

N-methyl-4-(3-(4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)- benzamide 6B  89

N-methyl-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A 90

4-(3-(4-(7-(furan-2-yl)-4- morpholino-pyrido[3,2- d]pyrimidin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A  91

4-(3-(2-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D  92

4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A  93

N,N-dimethyl-4-(3-(4-(7-(4- methylpyridin-3-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A 94

4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A  95

4-(3-(4-(7-(6- methoxypyridin-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B  96

N,N-dimethyl-4-(3-(4-(4- morpholino-7-(pyridazin-4-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)- benzamide  7  97

4-(3-(2-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 98

4-(3-(2-fluoro-4-(4- morpholino-7-(pyridazin-4- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6 + 6D  99

4-(3-(2-fluoro-4-(6-fluoro- 4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G + 6D 100

4-(3-(2-fluoro-4-(7-(4- methylpyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 101

4-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)-N,N- dimethyl-benzamide7B 102

4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-3- yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 7B 103

4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 104

4-(3-(2-fluoro-4-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide 7B 105

4-(3-(2-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D106

4-(3-(2-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7B 107

4-(3-(4-(6-fluoro-7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G 108

4-(3-(2-fluoro-4-(6-fluoro- 7-(1-methyl-1H-pyrazol-4- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido dimethyl- benzamide)-N,N-dimethyl-benzamide 6D + 6G 109

4-(3-(2-fluoro-4-(6-fluoro- 4-morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D + 6G 110

4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholino-quinazolin-2-yl)-2-fluorophenyl)ureido)- N,N-dimethyl-benzamide 6D 111

4-(3-(5-(7-(2-fluoropyridin- 3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide 7A + 6E 112

4-(3-(5-(6-fluoro-7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)- N,N-dimethyl-benzamide 6E + 6G 113

4-(3-(5-(6-fluoro-7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2- yl)pyridin-2-yl)ureido)- N,N-dimethyl-benzamide6E + 6G 114

4-(3-(2-fluoro-4-(7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 115

N,N-dimethyl-4-(3-(5-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-pyrido[3,2- d]pyrimidin-2-yl)pyridin-2- yl)ureido)-benzamide7A + 6E 116

4-(3-(2-fluoro-4-(7-(4- methylpyridin-3-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7B 117

4-(3-(2-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyureido)-N,N- dimethyl-benzamide 7B 118

4-(3-(2-fluoro-4-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D119

4-(3-(5-(7-(2- methoxypyrimidin-5-yl)-4- morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)- N,N-dimethyl-benzamide 6E 120

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A 121

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 122

5-(3-(2-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethylpicolinamide 6B + 4 123

5-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethylpicolinamide 6B + 4 124

5-(3-(2-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethylpicolinamide 7A + 4 125

4-(3-(4-(4-(2,6- dimethylmorpholino)-7-(1- methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 7 126

4-(3-(4-(4-(2,6- dimethylmorpholino)-7-(1- methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin- 2-yl)-2- fluorophenyl)ureido)-N,N-dimethyl-benzamide  7 127

4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2-yl)-2- fluorophenyl)ureido)-N,N- dimethyl-benzamide 7B 128

4-(3-(4-(4-(2,6- dimethylmorpholino)-7- (pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 129

N,N-dimethyl-5-(3-(5-(7-(5- methylfuran-2-yl)-4-morpholino-quinazolin-2- yl)pyridin-2- yl)ureido)picolinamide  6 130

5-(3-(2-fluoro-4-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethylpicolinamide6B + 4 131

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-quinazolin-2-yl)-2-fluorophenyl)ureido)- N,N-dimethyl-benzamide 6D 132

4-(3-(4-(4-(2,6- dimethylmorpholino)-7- (pyrimidin-5-yl)quinazolin-2-yl)-2- fluorophenyl)ureido)-N,N- dimethyl-benzamide  6 133

3-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin- 2-yl)phenyl)ureido)- benzamide 6C 134

3-fluoro-N,N-dimethyl-4- (3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino- pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-benzamide 7A 135

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2-yl)-2- fluorophenyl)ureido)-N,N- dimethyl-benzamide 7B 136

3-fluoro-N,N-dimethyl-4- (3-(4-(7-(5-methylfuran-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6C 137

4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-4- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 138

N,N-dimethyl-4-(3-(4-(4-(2- methylmorpholino)-7-(pyrimidin-5-yl)quinazolin- 2-yl)phenyl)ureido)- benzamide  6 139

3-fluoro-4-(3-(2-fluoro-4- (4-morpholino-7- (pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 140

3-fluoro-N,N-dimethyl-4- (3-(5-(4-morpholino-7-(pyrimidin-5-yl)quinazolin- 2-yl)pyridin-2-yl)ureido)- benzamide 6E 141

3-fluoro-4-(3-(2-fluoro-4- (7-(1-methyl-1H-pyrazol-4- yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A142

N,N-dimethyl-4-(3-(4-(7-(5- methylfuran-2-yl)-4-(2-methylmorpholino)quinazolin- 2-yl)phenyl)ureido)- benzamide  6 143

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-6- fluoro-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G 144

4-(3-(2-fluoro-4-(4-(2- methylmorpholino)-7- (pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 145

3-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A 146

3-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6C 147

3-fluoro-4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6C148

N,N-dimethyl-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-(2-methylmorpholino) pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-benzamide  7 149

4-(3-(4-(6-fluoro-7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G 150

4-(3-(4-(7-(2- hydroxypyrimidin-5-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 151

4-(3-(2-fluoro-4-(7-(6- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6D 152

3-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)- benzamide 6C 153

3-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A154

3-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide7A 155

N,N-dimethyl-4-(3-(4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)- benzamide 6 + 6B 156

4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6 + 6D 157

3-fluoro-4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A 158

1-(4-(7-(furan-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)-3-(4-(4-methylpiperazine-1- carbonyl)phenyl)urea 6B 159

4-(3-(5-(7-(furan-2-yl)-4- morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)- N,N-dimethyl-benzamide 6E 160

3-fluoro-4-(3-(4-(7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6C 161

N,N-dimethyl-4-(3-(4-(7-(6- methylpyridin-3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6B 162

N,N-dimethyl-4-(3-(4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)- benzamide 6B 163

4-(3-(4-(7-(2- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 164

4-(3-(4-(7-(5-fluoropyridin- 3-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 165

N,N-dimethyl-4-(3-(4-(7-(2- methylpyridin-3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6B 166

3-fluoro-N,N-dimethyl-4- (3-(4-(7-(6-methylpyridin- 3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6C 167

3-fluoro-N,N-dimethyl-4- (3-(4-(7-(2-methylpyridin- 3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6C 168

3-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2- yl)phenyl)ureido)- benzamide 6 + 6C 169

4-(3-(4-(7-(4- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 170

3-fluoro-4-(3-(4-(7-(6- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6C 171

3-chloro-4-(3-(4-(7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 172

3-fluoro-N,N-dimethyl-4- (3-(5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino- quinazolin-2-yl)pyridin-2-yl)ureido)-benzamide 6E 173

3-fluoro-4-(3-(4-(6-fluoro- 4-morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G 174

3-fluoro-4-(3-(4-(6-fluoro- 4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6G 175

4-(3-(5-(6-fluoro-4- morpholino-7-(pyridin-3-yl)quinazolin-2-yl)pyridin- 2-yl)ureido)-N,N-dimethyl- benzamide 6G + 6E176

4-(3-(5-(6-fluoro-4- morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)pyridin- 2-yl)ureido)-N,N-dimethyl- benzamide 6G + 6E177

4-(3-(4-(7-(6-aminopyridin- 3-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 178

4-(3-(4-(7-(6-aminopyridin- 3-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-3-fluoro- N,N-dimethyl-benzamide 6C 179

N,N-dimethyl-4-(3-(4-(4- morpholino-quinazolin-2- yl)phenyl)ureido)-benzamide 15 180

4-(3-(4-(7-methoxy-4- morpholino-quinazolin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide 15 181

4-(3-(4-(6,7-dimethoxy-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 15 182

4-(3-(2-fluoro-4-(7- methoxy-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 15 183

4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6b 184

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4- yl)-4-morpholino- pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea 7A, 13 + 14 185

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4- yl)-4-morpholino- pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea 7A, 13 + 14 186

1-(4-(4- (dimethylamino)piperidine- 1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)- 4-morpholino-pyrido[3,2- d]pyrimidin-2-yl)phenyl)urea 7A, 13 + 14 187

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(4-morpholino-7- (pyrimidin-5-yl)quinazolin- 2-yl)phenyl)urea 6B, 13 +14 188

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(4-morpholino-7- (pyrimidin-5-yl)quinazolin- 2-yl)phenyl)urea 6B, 13 +14 189

1-(4-(3-hydroxypyrrolidine- 1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5- yl)quinazolin-2- yl)phenyl)urea 6B, 13 + 14190

4-(3-(4-(7-(5- ((dimethylamino)methyl)furan- 2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6B 191

1-(4-(4- (dimethylamino)piperidine- 1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 6B, 13 +14 192

N-(2- (dimethylamino)ethyl)-4-(3- (4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin- 2-yl)phenyl)ureido)- benzamide 6B , 13 + 14193

1-(4-(4- (dimethylamino)piperidine- 1-carbonyl)phenyl)-3-(4-(7-(4-methylpyridin-3-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 6B,13 + 14 194

(S)-1-(4-(3- aminopyrrolidine-1- carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5- yl)quinazolin-2- yl)phenyl)urea 6B, 13 + 14195

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 6B,13 + 14 196

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 6B,13 + 14 197

(R)-1-(4-(3- aminopyrrolidine-1- carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5- yl)quinazolin-2- yl)phenyl)urea 6B, 13 + 14198

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(6-fluoro-4-morpholino-7- (pyridin-3-yl)quinazolin-2- yl)phenyl)urea 6G,13 + 14 199

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(4-morpholino-7- (pyrimidin-5-yl)pyrido[3,2- d]pyrimidin-2-yl)phenyl)urea 7A, 13 + 14 200

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(6-fluoro-4-morpholino-7- (pyridin-3-yl)quinazolin-2- yl)phenyl)urea 6G,13 + 14 201

N-(2- (dimethylamino)ethyl)-4-(3- (4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6B, 13 + 14 202

4-(3-(4-(7-(1-methyl-1H- pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A, 13 + 14 203

4-(3-(2-fluoro-4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6D 204

1-(4-(3-hydroxypyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 6B, 13 +14 205

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(2-fluoro-4-(7-(1-methyl-1H- pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)urea 7A, 13 + 14 206

4-(3-(4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6B 207

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7- (pyrimidin-5-yl)quinazolin- 2-yl)phenyl)urea6B, 13 + 14 208

(S)-1-(4-(3- aminopyrrolidine-1- carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7- (pyrimidin-5-yl)quinazolin- 2-yl)phenyl)urea6B, 13 + 14 209

(R)-1-(4-(3- aminopyrrolidine-1- carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7- (pyrimidin-5-yl)quinazolin- 2-yl)phenyl)urea6B, 13 + 14 210

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(2-fluoro-4-(7-(1-methyl-1H- pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)urea 7A, 13 + 14 211

1-(2-fluoro-4-(6-fluoro-4- morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)- 3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea 6G, 13 + 14 212

1-(2-fluoro-4-(4- morpholino-7-(pyridin-4- yl)quinazolin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1- carbonyl)phenyl)urea 6B, 13 + 14 213

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(2-fluoropyridin-3-yl)-4- morpholino-pyrido[3,2- d]pyrimidin-2-yl)phenyl)urea 7A, 13 + 14 214

4-(3-(2-fluoro-4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- benzamide 11 + 6D 215

4-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N- methyl-benzamide 6B, 13 + 14 216

4-(3-(4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 7A 217

N-(2- (dimethylamino)ethyl)-4-(3- (2-fluoro-4-(4-morpholino-7-(pyrimidin-5- yl)quinazolin-2- yl)phenyl)ureido)- benzamide 6B, 13 +14 218

4-(3-(2-fluoro-4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 +7B 219

3-fluoro-4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6C 220

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(3,5-dimethylisoxazol-4- yl)-4-morpholino-quinazolin-2-yl)phenyl)urea 6B, 13 + 14 221

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(3,5-dimethylisoxazol-4- yl)-4-morpholino- quinazolin-2-yl)-2-fluorophenyl)urea 6B, 13 + 14 222

4-(3-(4-(7-(5-(2- hydroxypropan-2-yl)furan- 2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6B 223

4-(3-(4-(7-(5-cyanofuran-2- yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6B 224

4-(3-(4-(7-(5-acetylfuran-2- yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6B 225

N-(2- (dimethylamino)ethyl)-5-(2- (4-(3-(4- (dimethylcarbamoyl)phenyl)ureido)phenyl)-4- morpholino-quinazolin-7- yl)furan-2-carboxamide 11 +6B 226

4-(3-(4-(7-(2- (dimethylamino)pyrimidin- 5-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 227

3-fluoro-4-(3-(4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 +6C 228

3-fluoro-4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6C 229

5-(2-(4-(3-(4- (dimethylcarbamoyl)phenyl) ureido)phenyl)-4-morpholino-quinazolin-7- yl)-N,N-dimethylfuran-2- carboxamide 11 + 6B230

4-(3-(4-(7-(2- (dimethylamino)pyrimidin- 5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7A231

4-(3-(4-(7-(2- (dimethylamino)pyrimidin- 5-yl)-4-morpholino-quinazolin-2-yl)-2- fluorophenyl)ureido)-N,N- dimethyl-benzamide 6D 232

1-(4-(7-(furan-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)-3-(4-(3-hydroxypyrrolidine-1- carbonyl)phenyl)urea 6B, 13 + 14 233

4-(3-(4-(7-(furan-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)ureido)-N-methyl-benzamide 6B, 13 + 14 234

(S)-1-(4-(3- aminopyrrolidine-1- carbonyl)phenyl)-3-(4-(7-(furan-2-yl)-4-morpholino- quinazolin-2-yl)phenyl)urea 6B, 13 + 14 235

N-(2- (dimethylamino)ethyl)-4-(3- (4-(7-(furan-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide 6B , 13 + 14 236

N-(2- (dimethylamino)ethyl)-4-(3- (4-(7-(furan-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N- methyl-benzamide 6B , 13 +14 237

4-(3-(3-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 238

4-(3-(3-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)-N,N-dimethyl-benzamide  7 239

4-(3-(3-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 240

2-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin- 2-yl)phenyl)ureido)- benzamide  6 241

4-(3-(3-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 242

4-(3-(3-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  6243

4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 244

4-(3-(3-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  7 245

4-(3-(3-fluoro-4-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  6246

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-2-fluoro- N,N-dimethyl-benzamide  6 247

4-(3-(3-fluoro-4-(7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 248

2-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  7 249

4-(3-(3-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  6250

4-(3-(3-fluoro-4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 7 251

5-(3-(3-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethylpicolinamide  6 252

4-(3-(4-(7-(3,5- dimethylisoxazol-4-yl)-4- morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)- N,N-dimethyl-benzamide  6 253

2-fluoro-N,N-dimethyl-4- (3-(5-(7-(3- (methylsulfonyl)phenyl)-4-morpholino-quinazolin-2- yl)pyridin-2-yl)ureido)- benzamide 6 + 6E 254

4-(3-(3-fluoro-4-(4-(2- methylmorpholino)-7- (pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 255

2-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 256

4-(3-(3-fluoro-4-(6-fluoro- 4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6 + 6G 257

2-fluoro-4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  6258

4-(3-(3-fluoro-4-(7-(6- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 259

2-fluoro-4-(3-(4-(7-(6- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 260

2-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)- benzamide  6 261

4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-3- yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  7 262

2-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7 263

4-(3-(3-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4- morpholino-pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  7 264

2-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)- benzamide  7265

2-fluoro-4-(3-(4-(7-(furan- 2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 266

2-fluoro-N,N-dimethyl-4- (3-(4-(7-(5-methylfuran-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)- benzamide  6 267

2-fluoro-N,N-dimethyl-4- (3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2- yl)phenyl)ureido)- benzamide  6 268

4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 269

4-(3-(3-fluoro-4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 270

4-(3-(3-fluoro-4-(7-(2- methoxypyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 271

4-(3-(3-fluoro-4-(7-(6- methylpyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 272

4-(3-(3-fluoro-4-(7-(2- methylpyridin-3-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide  6 273

2-fluoro-N,N-dimethyl-4- (3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino- pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-benzamide  7 274

4-(3-(3-fluoro-4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6 275

4-(3-(3-fluoro-4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 +6 276

4-(3-(3-fluoro-4-(7-(5-(2- hydroxypropan-2-yl)furan- 2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6 277

4-(3-(4-(7-(2- (dimethylamino)pyrimidin- 5-yl)-4-morpholino-quinazolin-2-yl)-3- fluorophenyl)ureido)-N,N- dimethyl-benzamide  6 278

2-fluoro-4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 11 + 6 279

4-(3-(2,5-difluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 2 + 6 280

4-(3-(2,3-difluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 2 + 6 281

4-(3-(2,3-difluoro-4-(7-(5- methylfuran-2-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 2 + 6282

-(3-(2,3-difluoro-4-(7- (furan-2-yl)-4-morpholino- quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 2 + 6 283

4-(3-(4-(7-(2-((2- hydroxyethyl)amino)pyridin- 3-yl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B 284

4-(3-(4-(7-((4- hydroxypiperidin-1- yl)methyl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B + methodsrelated to 11 285

4-(3-(4-(7-(hydroxymethyl)- 4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 8A + 12 286

1-(4-(4- (dimethylamino)piperidine- 1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)-4- morpholino-quinazolin-2- yl)phenyl)urea 8A,13 + 12 287

4-(3-(4-(7-(4- (dimethylamino)piperidine- 1-carbonyl)-4-morpholino-quinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 8A 288

(R)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)- 4-morpholine-quinazolin-2- yl)phenyl)urea 8A,13 + 12 289

(S)-1-(4-(3- (dimethylamino)pyrrolidine- 1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)- 4-morpholine-quinazolin-2- yl)phenyl)urea 8A,13 + 12 290

4-(3-(2-fluoro-4-(7-(2- hydroxypropan-2-yl)-4- morpholino-quinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 8A, 12 + 6 291

N-(4-(3-(4-(4-morpholino- 7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl)- acetamide 10 292

1-(4-(7-(2-fluoropyridin-3- yl)-4- morpholinoquinazolin-2-yl)phenyl)-3-(4-(2- oxopyrrolidin-1- yl)phenyl)urea 10 293

N-(4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 294

N-(4-(3-(4-(7-(1-methyl- 1H-pyrazol-4-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 295

N,N-dimethyl-4-(3-(4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)- benzamide 7A 296

4-(3-(2-fluoro-4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin- 2-yl)phenyl)ureido)-N,N- dimethyl-benzamide7B 297

N,N-dimethyl-4-(3-(4-(7-(2- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A 298

4-(3-(2-fluoro-4-(7-(2- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7B 299

N,N-dimethyl-4-(3-(4-(7-(6- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)- benzamide 7A 300

4-(3-(2-fluoro-4-(7-(6- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 7B 301

N-(4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 302

N-(4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 303

N-(4-(3-(4-(4-morpholino- 7-(pyridin-3-yl)pyrido[3,2- d]pyrimidin-2-yl)phenyl)ureido)phenyl) acetamide 7A + 9 304

N-(4-(3-(4-(4-morpholino- 7-(pyridin-4-yl)pyrido[3,2- d]pyrimidin-2-yl)phenyl)ureido)phenyl) acetamide 7A + 9 305

N-(4-(3-(4-(4-morpholino- 7-(pyridin-2-yl)pyrido[3,2- d]pyrimidin-2-yl)phenyl)ureido)phenyl) acetamide 7A + 9 306

N-(4-(3-(4-(4-morpholino- 7-(pyrimidin-5- yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl) acetamide 7A + 9 307

N-(4-(3-(4-(4-morpholino- 7-(pyridazin-4- yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl) acetamide 7A + 9 308

N-(4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 309

N-(4-(3-(4-(7-(6- methoxypyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 310

N-(4-(3-(4-(7-(3- (methylsulfonyl)phenyl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 311

N-(4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 312

N-(4-(3-(4-(4-morpholino- 7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 313

N-(4-(3-(4-(7-(2- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 314

N-(4-(3-(4-(7-(6- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 315

N-(4-(3-(5-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2-yl)pyridin-2- yl)ureido)phenyl)acetamide 7A + 6E + 9 316

N-(4-(3-(5-(7-(1-methyl- 1H-pyrazol-4-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2-yl)pyridin-2- yl)ureido)phenyl)acetamide 7A + 6E + 9 317

4-(3-(4-(7-(5-ethylfuran-2- yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B + 11 318

4-(3-(4-(7-(5-(1,2- dihydroxyethyl)furan-2-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)-N,N- dimethyl-benzamide 6B +11 319

N-(4-(3-(4-(7-(5-ethylfuran- 2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 320

N-(4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 11 + 10 321

N-(4-(3-(4-(7-(5-(1- hydroxyethyl)furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 11 + 10 322

N-(4-(3-(4-(7-(5-(2- hydroxypropan-2-yl)furan- 2-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 11 + 10 323

N-(4-(3-(4-(7-(furan-2-yl)- 4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 324

N-(4-(3-(4-(4-morpholino- 7-(pyridin-3-yl)quinazolin- 2-yl)phenyl)ureido)phenyl) acetamide 10 325

N-(4-(3-(4-(4-morpholino- 7-(pyridin-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 326

N-(4-(3-(4-(4-morpholino- 7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6B + 10 327

N-(4-(3-(4-(4-morpholino- 7-(pyridazin-4- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6B + 10 328

N-(4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 329

N-(4-(3-(4-(7-(6- methoxypyridin-3-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 330

N-(4-(3-(4-(7-(3- (methylsulfonyl)phenyl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 331

N-(4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 332

N-(4-(3-(4-(4-morpholino- 7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 333

N-(4-(3-(4-(7-(2- methylpyridin-3-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 334

N-(4-(3-(4-(7-(6- methylpyridin-3-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 335

N-(4-(3-(5-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)pyridin-2- yl)ureido)phenyl)acetamide 6E + 9 336

N-(4-(3-(5-(7-(furan-2-yl)- 4-morpholinoquinazolin-2- yl)pyridin-2-yl)ureido)phenyl)acetamide 6E + 9 337

N-(4-(3-(5-(4-morpholino- 7-(pyrimidin-5- yl)quinazolin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide 6E + 9 338

N-(4-(3-(5-(7-(1-methyl- 1H-pyrazol-4-yl)-4- morpholinoquinazolin-2-yl)pyridin-2- yl)ureido)phenyl)acetamide 6E + 9 339

N-(4-(3-(4-(6-fluoro-7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 340

N-(4-(3-(4-(6-fluoro-7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 341

N-(4-(3-(4-(6-fluoro-4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 342

N-(4-(3-(4-(6-fluoro-4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 343

N-(3-fluoro-4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 344

N-(4-(3-(4-(7-(5-ethylfuran- 2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)-3- fluorophenyl)acetamide 10 + 11 345

N-(3-fluoro-4-(3-(4-(7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 346

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 347

N-(3-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 348

N-(3-fluoro-4-(3-(4-(7-(2- methylpyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 349

N-(3-fluoro-4-(3-(4-(7-(6- methylpyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 350

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6A + 10 351

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-4- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 352

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 353

N-(3-fluoro-4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 354

N-(4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)-3- fluorophenyl)acetamide 10 355

N-(3-fluoro-4-(3-(4-(7-(6- methoxypyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 356

N-(3-fluoro-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 357

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 358

N-(3-fluoro-4-(3-(4-(7-(3- (methylsulfonyl)phenyl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 359

N-(3-fluoro-4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 360

N-(3-fluoro-4-(3-(4-(7-(5- (1-hydroxyethyl)furan-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 361

N-(3-fluoro-4-(3-(4-(7-(5- (2-hydroxypropan-2- yl)furan-2-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 362

N-(2-fluoro-4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 363

N-(4-(3-(4-(7-(5-ethylfuran- 2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)-2- fluorophenyl)acetamide 10 + 11 364

N-(2-fluoro-4-(3-(4-(7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 365

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 366

N-(2-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 367

N-(2-fluoro-4-(3-(4-(7-(2- methylpyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 368

N-(2-fluoro-4-(3-(4-(7-(6- methylpyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 369

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 + 6A 370

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-4- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 371

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 372

N-(2-fluoro-4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 373

N-(4-(3-(4-(7-(2- aminopyrimidin-5-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)-2- fluorophenyl)acetamide 10 374

N-(2-fluoro-4-(3-(4-(7-(6- methoxypyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 375

N-(2-fluoro-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 376

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(1,3,5- trimethyl-1H-pyrazol-4-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 377

N-(2-fluoro-4-(3-(4-(7-(3- (methylsulfonyl)phenyl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 378

N-(2-fluoro-4-(3-(4-(7-(5- (hydroxymethyl)furan-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 379

N-(2-fluoro-4-(3-(4-(7-(5- (1-hydroxyethyl)furan-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 380

N-(2-fluoro-4-(3-(4-(7-(5- (2-hydroxypropan-2- yl)furan-2-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 + 11 381

N-methyl-N-(4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 382

N-(4-(3-(4-(7-(5-ethylfuran- 2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 + 11 383

N-(4-(3-(4-(7-(furan-2-yl)- 4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 384

N-(4-(3-(4-(7-(2- methoxypyrimidin-5-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 385

N-methyl-N-(4-(3-(4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 386

N-methyl-N-(4-(3-(4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 387

N-(4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 388

N-methyl-N-(4-(3-(4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6A + 10 389

N-(3-fluoro-4-(3-(4-(6- fluoro-7-(5-methylfuran-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 390

N-(3-fluoro-4-(3-(4-(6- fluoro-7-(furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 391

N-(3-fluoro-4-(3-(4-(6- fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 392

N-(3-fluoro-4-(3-(4-(6- fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 393

N-(2-fluoro-4-(3-(4-(6- fluoro-7-(5-methylfuran-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 394

N-(2-fluoro-4-(3-(4-(6- fluoro-7-(furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 10 395

N-(2-fluoro-4-(3-(4-(6- fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 396

N-(2-fluoro-4-(3-(4-(6- fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 10 397

N-(4-(3-(4-(6-fluoro-7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 398

N-(4-(3-(4-(6-fluoro-7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 399

N-(4-(3-(4-(6-fluoro-4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 400

N-(4-(3-(4-(6-fluoro-4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 10 401

N-(3-fluoro-4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 402

N-(3-fluoro-4-(3-(4-(7- (furan-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 403

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9404

N-(3-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 405

N-(3-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9406

N-(3-fluoro-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide7A + 9 407

N-(2-fluoro-4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 408

N-(2-fluoro-4-(3-(4-(7- (furan-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 409

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9410

N-(2-fluoro-4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 411

N-(2-fluoro-4-(3-(4-(4- morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9412

N-(2-fluoro-4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide7A + 9 413

N-methyl-N-(4-(3-(4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9 414

N-(4-(3-(4-(7-(furan-2-yl)- 4-morpholinopyrido[3,2- d]pyrimidin-2-yl)phenyl)ureido)phenyl)- N-methylacetamide 7A + 9 415

N-methyl-N-(4-(3-(4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9416

N-(4-(3-(4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl)- N-methylacetamide 7A + 9 417

N-methyl-N-(4-(3-(4-(4- morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7A + 9418

N-methyl-N-(4-(3-(4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide7A + 9 419

N-(4-(3-(2-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10 420

N-(4-(3-(2-fluoro-4-(7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10 421

N-(4-(3-(2-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10422

N-(4-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10 423

N-(4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10 424

N-(4-(3-(2-fluoro-4-(7-(2- fluoropyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10425

N-(4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6D + 9 + 10 426

N-(4-(3-(3-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10 427

N-(4-(3-(3-fluoro-4-(7- (furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10 428

N-(4-(3-(3-fluoro-4-(7-(2- methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10429

N-(4-(3-(3-fluoro-4-(4- morpholino-7-(pyrimidin-5- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10 430

N-(4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-3- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10 431

N-(4-(3-(3-fluoro-4-(7-(2- fluoropyridin-3-yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10432

N-(4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-2- yl)quinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 9 + 10 433

N-(4-(3-(2-fluoro-4-(6- fluoro-7-(5-methylfuran-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6G + 6D + 9 +10 434

N-(4-(3-(2-fluoro-4-(6- fluoro-7-(furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6G + 6D + 9 + 10 435

N-(4-(3-(2-fluoro-4-(6- fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6G +6D + 9 + 10 436

N-(4-(3-(2-fluoro-4-(6- fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6G + 6D +9 + 10 437

N-(4-(3-(3-fluoro-4-(6- fluoro-7-(5-methylfuran-2- yl)-4-morpholinoquinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6 + 6G + 9 +10 438

N-(4-(3-(3-fluoro-4-(6- fluoro-7-(furan-2-yl)-4- morpholinoquinazolin-2-yl)phenyl)ureido)phenyl) acetamide 6 + 6G + 9 + 10 439

N-(4-(3-(3-fluoro-4-(6- fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6 +6G + 9 + 10 440

N-(4-(3-(3-fluoro-4-(6- fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2- yl)phenyl)ureido)phenyl) acetamide 6 + 6G +9 + 10 441

N-(4-(3-(2-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7B + 9 + 10 442

N-(4-(3-(2-fluoro-4-(7- (furan-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7B + 9 + 10 443

N-(4-(3-(2-fluoro-4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7B + 9 +10 444

N-(4-(3-(2-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7B + 9 + 10 445

N-(4-(3-(2-fluoro-4-(4- morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7B + 9 +10 446

N-(4-(3-(2-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide7B + 9 + 10 447

N-(4-(3-(3-fluoro-4-(7-(5- methylfuran-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7 + 9 + 10 448

N-(4-(3-(3-fluoro-4-(7- (furan-2-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7 + 9 + 10 449

N-(4-(3-(3-fluoro-4-(4- morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7 + 9 +10 450

N-(4-(3-(3-fluoro-4-(7-(2- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7 + 9 + 10 451

N-(4-(3-(3-fluoro-4-(4- morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide 7 + 9 +10 452

N-(4-(3-(3-fluoro-4-(7-(1- methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2- d]pyrimidin-2- yl)phenyl)ureido)phenyl) acetamide7 + 9 + 10

Example 72 Biological Assays

(i) P13 Kinase Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

The ability of compounds of the invention to inhibit PI3K activity wasdetermined in a homogeneous TR-FRET assay using a PI3K assay kit(Millipore, USA; cat #33-016) according to manufacturer's instructions.PI3-Kinases (isoforms α, β, γ and δ) catalyze the phosphorylation ofphosphatidylinositol, PIP2 to PIP3 in the presence of ATP and Mg²⁺. ThePIP3 product is detected by displacement of biotin-PIP3 from an energytransfer complex consisting of Europium labeled anti-GST monoclonalantibody, a GST-tagged PH domain, biotinylated PIP3 andStreptavidin-APC. Excitation of Europium in the complex results in anenergy transfer to the APC and a fluorescence emission at 665 nm. ThePIP3 product displaces biotin-PIP3 from the complex resulting in a lossof energy transfer and thus a decrease in signal.

To test for the ability of compounds to inhibit the activity of PI3Kα(wild-type), exemplary compounds of formula (I) were dissolved in DMSOand directly distributed into 384-well plates at a volume of 0.5 μL.14.5 μL of P110/P85α/PIP2 mixture in buffer (obtained from the Milliporekit) containing MgCl₂ (40 mM) and DTT (5 mM) was added to compound wellsand incubated for 60 min at room temperature. P110/P85α was expressed inSF9 insect cells and purified nickel column extraction. Five ng ofwild-type P110/P85α was used in the assay. The kinase reaction wasstarted by the addition of ATP. The assay concentrations of both PIP2and ATP were 10 μM. The reaction mixture was incubated for 30 min atroom temperature and was terminated by the addition of stop mix anddetection mix. Fluorescence was measured at 615 and 665 nm uponexcitation at 340 nm in a Victor™ V5 fluorometer (Perkin Elmer, USA).The fluorescence emission ratio at 665 to 615 nm, proportional to thekinase activity, was plotted against the compound concentration togenerate dose-response curves and IC₅₀ values were determined usingGraphPad Prism® 5 software.

Inhibition of PI3Kα activity was observed for compounds of formula (I)as determined by this assay. See, Table 2.

The activity of PI3 kinase isoforms β, γ and δ were assayed in a similarmanner to the assay protocol described above for PI3Kα, by substitutingthe appropriate p110/p85 isoform for the p110α/p85α. Compounds offormula (I) caused inhibition of PI3 kinase isoforms β, γ and δ asdetermined by these assays. For example, the compounds of examples 3,51, 54, 111, 113, 115, and 253 each caused inhibition of PI3 kinaseisoform β with IC₅₀ values <50 nM. The compounds of examples 104, 133,146 and 152 each caused inhibition of PI3 kinase isoform β with IC₅₀values <500 nM. The compounds of examples 3, 51, 54, 104, 111, 113, 115,133, 253, and 152 each caused inhibition of PI3 kinase isoform γ withIC₅₀ values <500 nM. The compound of Example 2 caused inhibition of PI3kinase isoform β and isoform γ with IC₅₀ values <1 μM. The compounds ofexamples 2, 3, 51, 54, 111, 113, and 253 each caused inhibition of PI3kinase isoform δ with IC₅₀ values >1 μM.

The activity of PI3Kα mutations H1047R and E545K were assayed in asimilar manner to the assay protocol described above for PI3Kα (wildtype). The compounds of formula (I) caused inhibition of PI3Kα mutationsH1047R (a mutation associated with breast and gastric cancers) and E545K(a mutation associated with colorectal tumors, glioblastomas, gastriccancers, breast cancers, and lung cancers). For example, each of thecompounds of examples 1, 2, 3, 51, 54, 104, 111, 113, 115, and 253caused inhibition of each of the PI3Kα mutations H1047R and E545K withIC₅₀ values <50 nM. Each of the compounds of examples 133, 146, and 152caused inhibition of each of the PI3Kα mutations H1047R and E545K withIC₅₀ values <500 nM.

(ii) mTOR Kinase TR-FRET Assay

Compound inhibition for mTOR kinase was determined in a homogeneousTR-FRET assay using the Lance® ULight-p70 S6K (Thr 389) peptide(obtained from Perkin-Elmer). The ULight™-labeled synthetic peptidecontains the amino acid residues surrounding Thr389 of human p70 S6K.The ULight-p70 S6K peptide is phosphorylated at Thr389 by mTOR.Phosphorylation motif: LGFTYVAP as substrate.

The compound dilution was carried out in 100% DMSO followed by a bufferdilution. The reaction buffer was HEPES (50 mM pH 7.5), EGTA (1 mM),MnCl₂ (3 mM). Test compounds at various concentrations werepre-incubated with mTOR (Millipore, USA; 5 ng) for 60 min, and then theLance® ULight-p70 S6K (Thr 389) peptide (50 nM) was added along with ATP(20 μM). After incubating the reaction mixture for 60 min at roomtemperature, the kinase reaction was terminated by the addition of EDTA(10 mM) followed by the addition of detection mix, i.e., 1 nM Eu-labeledanti-phospho-substrate antibody (Perkin Elmer, USA). The fluorescenceemission at 615 and 665 nM was measured upon excitation at 340 nM. IC₅₀values were subsequently determined using a sigmoidal dose-responsecurve (variable slope) in GraphPad Prism® 5 software.

Compounds of formula (I) caused inhibition of mTOR kinase activity asdetermined by this assay. See Table 2.

(iii) In-Cell Western Assay

Cells from human prostate cancer cell line PC3 (American Type CultureCollection (ATCC), Manassas, Va. 20108 USA) were seeded at an optimaldensity of 22,000 cell/well in 96-well plates containing Ham's F12Kmedium (90 μL) and incubated overnight. The compound dilutions werecarried out in 100% DMSO followed by a dilution in the medium. Testcompounds were added in serial dilutions to the wells and incubated for2 h. The cells were washed and fixed with 4% paraformaldehyde. Afterincubation at room temperature for 1 h in the dark, blocking was donefor 2 h at room temperature. Primary antibodies for phosphorylated (p)AKT(S473) (phosphorylated at serine 473), pAKT(T308) (phosphorylated atthreonine 308) and for pS6RP(S235/236) (phosphorylated at serine235/236) (commercially available from Cell Signaling Technology®, whoseprotocol was followed for the in-cell western assay, were diluted to therequired concentration and added to the corresponding wells followed byovernight incubation at 4° C. Eu-labeled rabbit (PE) (Perkin-Elmer USAcatalog #AD0106) secondary antibody was added and incubated for 2 h atroom temperature. Delfia® enhancement solution (cat #1244-105, PerkinElmer USA) was subsequently added to the plate before taking the readingat 615 nm with excitation wavelength of 340 nm, after which 0.5 μg/mL ofHoechst® 33258 dye (Catalog #86140-5, Sigma) was added to the plate andfluorescence emission was read at 460 nm with 355 nm excitation, toevaluate the correction factor. IC₅₀ values were calculated using asigmoidal dose-response curve fit in GraphPad Prism® v5 software.Compounds of formula (I) inhibited phosphorylation of Akt(S473),Akt(T308) and S6RP, as shown in Table 2. These results indicate theability of the tested compounds to inhibit an PI3K/Akt-pathway dependentprostate neoplasm.

In-cell Western assays for pAkt(S473) and pS6RP are also carried out ina breast cancer cell line with PI3K mutations (PIK3CA-K111N mutation)which overexpresses HER 2 (BT474) cells and a human ductal breastepithelial cell line (T47D cells), in a similar manner to the protocoldescribed above for PC3 cells, in order to assess the ability of thecompounds to inhibit the Akt-pathway in two breast cancer cell lines.Compounds of the invention caused inhibition of pAkt(S473) and pS6RP inBT474 and T47D cell lines as determined by these assays. For example,the compound of Example 1 caused inhibition of pAkt(S473) in BT474 andT47D cell lines with IC₅₀ values <300 nM, and this compound also causedinhibition of pS6RP in BT474 and T47D cell lines with IC₅₀ values <50nM.

(iv) XTT Assay for Cell Viability

Using a commercial kit from Sigma Aldrich (Catalog #X34251) andfollowing its protocol, PC3 cells in the log phase of growth wereemployed and seeded at an optimal density of 1000 cell/well on to 96well plates and incubated for 24 h followed by the addition of compoundsof formula (I) in serial dilutions. Compound dilutions were made inDMSO. The cells were incubated with the compounds of formula (I) for 96h and XTT tetrazolium dye (Sigma, USA) was subsequently added andincubated at 37° C. After the color formation, absorbance was measuredat 465 nm in a Spectramax® Gemini spectrophotometer. EC₅₀ values werecalculated using a sigmoidal dose response curve fit in GraphPad Prism®v5 software. The tested compounds of formula (I) which caused inhibitionof PC3 cell proliferation as determined by this assay protocol are shownin Table 2.

XTT assays for cell viability are also determined in BT474 cells andT47D cells, in a similar manner to the protocol described above. Thecompounds caused inhibition of BT474 and T47D cell proliferation asdetermined by these assays. For example, the compound of Example 1caused inhibition of BT474 and T47D cell proliferation with IC₅₀ values<100 nM.

(v) In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Studies for Oncology

PC3 cells were cultured at 37° C. in a 5% CO₂ incubator using Hams F12 Kmedium. Ten million (10⁷) cells were injected subcutaneously to theright flank region of athymic male mice (Harlan, age: 6-7 weeks, weight:about 20 g). Tumor bearing mice were randomized when the tumor volumereached about 250 mm³ and three mice were used per each time point. Testcompounds of formula (I) were formulated in 40% HPCD in lx PBS, pH 7.4and dosed orally at 50 mg/kg single dose (dose volume −10 mL/kg). Plasmaand tumor samples were collected at 0 (vehicle control animals), 1, 4and 24 hours post dosing. Blood was drawn (retro orbital) to a tubecontaining 0.2% EDTA for plasma collection. The tumor was excised fromthe mouse and immediately frozen in liquid nitrogen for PD analysis.Tumor and plasma drug concentrations were measured for PK analysis usingLC-MS.

Snap frozen tumor samples were pulverized in a mortar (Belart)containing liquid nitrogen and tumor powder was stored at −80° C. untilanalysis. Pre coated ELISA kits (Cell Signaling Technology; pAKT(T308),CST#7135; pAKT(S473), CST#7134 and pS6RP, CST#7205) were used for PDanalysis. Tumor powder was transferred to Eppendorf® tubes and lysisbuffer (1 mL) was added to the powder. Protease and phosphataseinhibitors (SIGMA) and phenylmethanesulfonylfluoride (PMSF) were addedto tumor powder and mixed by vortexing followed by sonication (15 sec).Samples were kept on an ice bath for 30 min. Supernatant was separatedafter centrifugation at 10,000 rpm for 20 min at 4° C. Supernatant wasre-centrifuged and fresh supernatant was aliquoted to different tubes.Total protein was estimated using a BCA kit (Thermo Scientific) and 50μg total protein was loaded to each well. ELISA analysis was carried outas per manufacturer's instructions. The detection for pAKT was based onchemiluminescence and pS6RP was based on absorbance. Qualitativeassessments of the suppression of pAKT(T308), pAKT(S473), and pS6RP werealso carried out by standard Western blot analyses.

The compounds caused suppression of pAkt and pS6RP as measured at 1, 4and 24 hours after a single dose of 30-50 mg/kg po. For example, thecompound of Example 1, at 50 mg/kg po, caused about 50% inhibition ofpAkt(S473) at 1 and 4 hours and >50% inhibition of pS6RP at 1, 4 and 24hours. Also, the compound of Example 2, at 50 mg/kg po, caused about25-30% inhibition of pAkt(S473) at 4 and 24 hours and >50% inhibition ofpS6RP at 1, 4 and 24 hours. The compound of example 51, at 30 mg/kg po,caused >50% inhibition of pS6RP at 2, 4 and 24 hours. Also, thecompounds of examples 133, 146, 147, and 228, at 50 mg/kg po, eachcaused >50% inhibition of pS6RP at 3 and 8 hours. The compounds ofexamples 133 and 146, at 50 mg/kg po, each showed significantsuppression of pAkt(T308) at 8 hours by Western blot analysis.

In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies were alsocarried out using BT474 tumor cells and the corresponding tumor-bearingxenograft mice, and compounds of the invention were determined to beactive in this assay. For example, the compound of example 51, at 30mg/kg po, caused 30-40% inhibition of pS6RP at 4 and 24 hours. Afterdosing the compounds for 2 weeks at 40 mg/kg bid po, the compounds ofexamples 2 and 51 caused significant suppression of pAkt(T308),pAkt(S473) and pS6RP in tumor tissue samples by Western blot analyses.

(vi) In Vivo Efficacy Studies for Oncology (Tumor Growth Suppression)

PC3 cells were cultured at 37° C. in a 5% CO₂ incubator using Hams F12 Kmedium. Five million (5×10⁶) cells were implanted subcutaneously to theright flank of athymic male mice (Harlan, age: 6-7 weeks, weight: about20 g). Tumor bearing mice were randomized when the tumor volume reachedabout 100 mm³. Ten mice were used per group. Dosage regimen of compoundsof formula (I) were scheduled on the basis of the PK, PK-PD and maximumtolerated dose studies. Compounds of formula (I) were formulated usingHPCD in PBS, pH 7.4 and dosed orally (dose volume, 10 mL/kg). Solutionsof the compounds were prepared immediately before dosing the animals. Avehicle control and a reference compound were included along with testcompounds.

The tumor size was measured on alternate days using Vernier® calipers.Assuming tumors to be ellipsoid, the tumor volume was calculated usingthe formula:V=(D×d ²)/2

where:

-   -   V (mm³) is tumor volume    -   D is longest diameter in mm    -   d is shortest diameter in mm.

Changes in tumor volume (Δ volumes) for each treated (T) and control (C)group were calculated by subtracting the mean tumor volume on the firstday of treatment (starting day) from the mean tumor volume on thespecified observation day. These values were used to calculate apercentage growth (% T/C) using the formula:% T/C=(ΔT/ΔC)×100

where ΔT>0, or% T/C=(ΔT/ΔTi)×100

where ΔT<0 and Ti is the mean tumor volume at the start of theexperiment.

Percentage tumor growth inhibition was calculated as [100−% T/C].Percentage body weight change was calculated as [(Body weight onspecified observation day−Body weight on starting day)/Body weight onstarting day]×100. The compounds suppressed tumor growth in this in vivoefficacy model. For example, the compound of Example 1 caused more than70% tumor growth inhibition as measured relative to vehicle controlgroup, after 14 days of dosing at 60 mg/kg qd po or at 30 mg/kg bid po,and the compound of Example 2 caused more than 70% tumor growthinhibition as measured relative to vehicle control group after 14 daysof dosing at 30 or 60 mg/kg qd po. The compounds of examples 82 and 183each caused about 60% tumor growth inhibition as measured relative tovehicle control group after 14 days of dosing at 40 mg/kg bid po.

In vivo efficacy studies were also carried out using BT474 tumor cells,in a similar manner to the protocol described above for the PC3 tumorcell in vivo efficacy study. Compounds of the invention suppressed tumorgrowth in the in vivo BT474 efficacy model. For example, relative tovehicle control group after 14 days of dosing, the compound of Example 2at 40 mg/kg bid po caused about 65% tumor growth inhibition, and thecompound of example 51 at 40 mg/kg bid po caused about 70% tumor growthinhibition.

(vii) In Vivo Efficacy Studies for Inflammation

The ability of compounds of the invention to reduce inflammation isdetermined by using various animal models that are known in the art.Some examples are as follows:

(a) Inflammatory arthritis. The ability of compounds of the invention toreduce inflammation in inflammatory arthritis is determined by followingprocedures for the collagen-induced arthritis (CIA) mouse model. See,e.g., the procedure described in Camps et al., Nature Med. 2005, 11,936-943, which is incorporated herein by reference.

(b) Pulmonary fibrosis. The ability of compounds of the invention toprevent bleomycin-induced pulmonary fibrosis in rats is determined byfollowing the procedures described in Wei et al., Biochem. Biophys. Res.Comm. 2010, 397, 311-317 and Brent et al., Toxicology 2000, 147, 1-13,which are incorporated herein by reference.

(c) Myocardial infarction. The ability of compounds of the invention toreduce inflammation and/or improve healing after myocardial infarctionis determined by following the procedures for a mouse model described inSiragusa et al., Circ. Res. 2010, 106, 757-768, which is incorporatedherein by reference.

(d) Peritonitis. The ability of compounds of the invention to reduceinflammation in peritonitis is determined by following procedures forthe RANTES-induced or thioglycollate-induced peritonitis mouse model,for example as described in Camps et al., Nature Med. 2005, 11, 936-943,which is incorporated herein by reference.

TABLE 2 Data for the Compounds of Examples 1-294 LC − MS LC − ret. MStime mTO pAkt- pAkt- Ex. M + H⁺ (min) PI3Kα R T308 S473 pS6RP XTT 1575.1 0.26 A A F E D E 2 576.7 0.64 A A E E E D 3 652.2 0.71 A B E 4647.2 0.11 A A D 5 588.8 0.64 B A D 6 591.9 1.53 B A E 7 611.1 0.08 B A8 595.2 1.28 C B 9 576.2 0.28 A A D 10 607.2 0.63 A A 11 689.3 0.10 A A12 606.2 1.17 A A 13 623.2 0.45 A A 14 614.2 0.63 A A 15 626.2 0.92 A A16 555.1 0.17 A A C C 17 563.1 0.64 B B E 18 589.2 0.13 C A 19 651.20.44 A A E E D D 20 637.0 0.44 A A E E E E 21 592.1 0.49 B A E 22 577.20.35 A A E E D D 23 666.2 0.55 A B F 24 574.2 0.19 A A E E D D 25 622.90.37 B B F 26 647.0 0.23 A A D 27 632.0 0.21 B A D 28 592.9 0.28 B A D29 592.0 0.38 A A D 30 592.9 0.35 A A D 31 651.8 0.34 B A E 32 705.90.21 A A F 33 629.2 0.10 A A E E D D 34 652.2 0.10 A A D 35 595.2 0.40 AA E E D D 36 668.8 0.72 A A D 37 633.9 0.23 B B E 38 669.1 0.80 A A D 39651.7 0.61 A A D 40 591.9 1.43 B A D E 41 589.2 0.27 A B D E 42 578.20.36 A A E D E D 43 578.1 1.18 A A E 44 632.2 0.09 A A D D D D 45 602.70.26 A A D 46 575.0 0.37 A A E D D D 47 590.7 0.87 B C 48 602.9 1.35 B B49 629.8 0.39 A A E E D D 50 615.7 0.54 A B 51 563.1 1.49 A A F E 52579.1 0.64 A B E 53 562.7 0.42 B B E 54 592.7 0.65 A B E 55 577.9 0.30 AA D E 56 563.0 0.70 B A 57 578.0 1.26 A C 58 573.8 0.27 A A F 59 624.20.45 A A D 60 603.8 0.44 A A E 61 593.2 1.22 B C 62 588.3 0.11 A A D E63 634.2 0.11 A A E E 64 613.2 1.28 C C 65 592.2 0.27 A A D E 66 631.20.12 A A D E 67 631.3 0.08 A A E 68 592.2 0.39 A A F 69 629.2 0.10 A A DE 70 632.3 0.16 B B F 71 577.2 1.62 B A 72 631.2 0.10 A A D E 73 633.30.16 A A F 74 579.2 0.71 A B F 75 605.1 0.45 A A D 76 590.1 0.29 A A 77674.4 0.16 A A 78 593.2 1.20 A A 79 630.8 0.10 C A F 80 563.1 1.49 A A DD 81 676.0 0.10 A A D F 82 596.2 0.52 A A C C 83 634.3 0.14 B A C C 84593.2 0.25 B A C C 85 579.1 0.46 A A C C 86 575.2 0.13 B A C C 87 595.21.32 B A D D 88 561.1 0.13 B A D C 89 564.2 0.21 A A C C 90 564.2 0.73blank 91 610.2 0.69 A A C C 92 591.2 0.17 A A C C 93 589.3 0.18 A A C C94 606.2 0.35 A A C C 95 604.3 1.34 B B F D 96 576.2 0.24 A A C C 97595.2 0.31 A A C C 98 593.2 0.25 B A C C 99 611.3 0.80 A A C C 100 606.30.19 A A C C 101 594.3 0.61 A A C C 102 593.5 0.73 A A C C 103 592.20.28 A A C C 104 670.2 1.30 A A D C C 105 623.2 0.44 B A C C 106 611.31.37 A A C C 107 610.3 0.81 A A C C 108 613.2 0.68 B A 109 610.2 0.81 BB 110 608.2 0.21 C A 111 594.3 1.38 A A C C C 112 611.2 1.43 A C F D 113596.3 0.64 A B D D C 114 581.3 1.09 B B 115 653.3 1.30 A B C C 116 607.20.49 B B F 117 624.2 1.43 A A C D 118 669.1 0.77 A A F C C 119 606.30.45 A C 120 593.2 0.65 A A C C 121 592.2 0.42 A A C C 122 596.2 0.86 BB 123 594.2 0.18 B A C C 124 597.4 0.17 A A C 125 606.3 0.80 C B 126624.2 1.30 C C 127 609.1 0.36 A A C C 128 603.4 0.48 C A C D 129 579.30.86 A B D F 130 670.2 0.40 A A C C 131 610.3 0.74 A B C C 132 621.40.74 C B C C 133 593.2 0.20 A A D F C C 134 596.2 0.35 A A C C 135 611.21.39 A A C 136 595.2 1.36 C C 137 592.2 0.24 B B C C 138 589.4 0.36 A AC 139 611.2 049 C C 140 594.4 0.42 A C 141 614.2 0.80 C B 142 591.3 1.44B B 143 610.2 1.04 B A C 144 607.2 0.57 B A 145 611.2 0.92 A A 146 610.20.55 B A D D C 147 623.2 0.37 B A C D 148 592.2 0.36 A A 149 581.2 1.21B B 150 591.2 0.24 A A 151 622.2 0.57 B B 152 592.2 0.20 A A D F D 153593.5 0.38 A A 154 594.3 0.32 A A 155 574.2 0.35 A A D C 156 592.4 0.49B B 157 624.2 0.52 A A 158 618.4 0.13 A B 159 563.8 0.13 A C D D 160581.5 0.77 A B F D 161 588.4 0.10 A A 162 605.4 0.20 A A 163 603.8 0.38A A 164 591.9 0.27 A A 165 588.2 0.12 A A 166 606.3 0.17 A A 167 606.20.10 A A 168 592.3 0.34 A A 169 603.8 0.11 A A 170 621.8 0.52 A B 171597.1 0.14 C C 172 596.3 0.29 A C 173 610.3 0.35 A A 174 611.3 0.30 B A175 593.3 0.63 A B 176 594.4 0.44 A B 177 589.2 0.09 A A 178 607.3 0.09B A 179 497.2 0.17 B A C C 180 527.2 0.22 A A C C 181 557.3 0.27 B A C C182 545.2 0.35 B A 183 593.1 0.23 A A C C 184 647.2 0.11 A A C C 185647.3 0.08 A A C C 186 661.3 0.10 A A C C 187 644.1 0.09 A A C C 188644.3 0.07 A A C C 189 617.2 0.11 C A C C 190 619.9 0.09 B A C C 191660.3 0.18 C B C C 192 618.3 0.10 B A 193 617.3 0.09 A A C C 194 616.30.07 A A C C 195 646.5 0.17 B A D 196 646.3 0.25 B A D D 197 616.3 0.08A A C C 198 661.5 0.10 A A C C 199 645.4 0.08 A A C C 200 661.3 0.13 A AC C 201 620.3 0.35 B A F F 202 550.3 0.28 A A C C 203 611.3 0.34 A A C C204 619.2 0.51 A A D D 205 665.4 0.10 A A C C 206 607.3 0.35 A A C C 207662.3 0.11 A A C D 208 634.2 0.11 A A C C 209 634.3 0.10 A A C C 210665.3 0.14 A A C C 211 665.4 0.22 A A C D 212 647.4 0.09 B B 213 680.30.33 A A C C 214 625.2 0.48 A A C D 215 579.4 0.21 B B C C 216 608.20.45 A A C C 217 636.1 0.08 A A C C 218 612.1 0.81 A B 219 611.2 0.44 BB 220 661.4 0.19 B A C C 221 679.4 0.21 B B 222 621.1 1.15 A A C C 223588.2 1.34 A A C C 224 604.9 1.04 A A C C 225 677.2 0.51 B A 226 618.30.40 A A C 227 625.2 0.41 C B 228 611.2 0.34 A A F 229 634.2 0.36 A A230 619.1 0.58 A A 231 636.3 0.83 B A 232 605.1 0.30 A A 233 549.7 0.55A B D 234 603.8 0.11 A A C 235 606.7 0.20 A A 236 620.6 0.19 A A 237593.2 0.19 A A C C 238 596.3 0.50 A A C C 239 595.2 1.23 B B 240 593.20.23 A A C 241 610.1 0.71 A B C C 242 623.2 0.42 A A C C 243 592.2 0.32A A C C 244 611.3 1.03 A A C C 245 669.1 0.70 A B C 246 610.2 0.62 B A CC 247 581.2 0.66 B B C C 248 611.2 1.16 A A 249 595.2 0.29 B A 250 594.20.28 A A C 251 594.2 0.14 C A 252 610.1 1.33 B B 253 670.2 1.00 A C D254 607.2 0.28 C B 255 610.2 0.70 B A C 256 611.2 0.33 B B C 257 623.20.46 A A C 258 622.2 0.88 B B 259 622.2 0.56 B A C 260 592.3 0.30 A A C261 593.2 0.31 A A 262 593.7 0.16 A A 263 624.2 0.46 A A 264 592.8 0.28A A 265 581.4 0.95 B B D 266 595.2 1.28 B B 267 592.4 0.50 A A F C 268592.4 0.40 A A F C 269 623.4 0.26 A A 270 621.8 0.44 B B 271 605.8 0.12A A 272 606.3 0.11 A B 273 595.9 0.29 A A 274 611.1 0.60 A B C 275 625.10.72 B A C 276 639.2 0.61 B B 277 636.3 0.62 A A 278 611.2 0.40 A A 279611.2 0.22 B B 280 611.2 0.37 B A D 281 613.4 1.30 C C 282 599.4 1.18 BC D 283 633.3 0.12 C B C C 284 610.6 0.14 C B 285 527.1 0.09 A A C D 286638.2 0.08 A A C C 287 650.9 0.10 C C 288 624.0 0.07 B A 289 623.8 0.07B A C C 290 573.3 0.24 B A 291 561.2 0.12 A A F E E 292 604.2 0.34 A 293579.2 0.73 A A 294 564.2 0.19 A A Activities (nM): A: IC₅₀ < 50; B: IC₅₀= 50-200; C: IC₅₀ = 201-10,000; D: IC₅₀ < 100; E: IC₅₀ = 100-500; F:IC₅₀ = 501-5000.

All publications cited in this specification are incorporated herein byreference. While the invention has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A compound of formula (I):

wherein: R¹ is H, F, Cl, or OCH₃; R² is H, optionally substituted aryl,optionally substituted heterocycle, optionally substituted heteroaryl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkylamino, optionallysubstituted dialkylamino, optionally substituted arylamino, optionallysubstituted heteroarylamino, optionally substituted heterocycle-amino,optionally substituted alkylcarbonylamino, optionally substitutedalkylsulfonylamino, optionally substituted alkylthio, optionallysubstituted alkylsulfonyl, optionally substituted alkoxy, optionallysubstituted hydroxyalkyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycle-oxy,optionally substituted alkylaminocarbonyl, optionally substitutedarylaminocarbonyl, optionally substituted heteroarylaminocarbonyl,optionally substituted heterocycle-aminocarbonyl, or C(O)-(optionallysubstituted heterocycle) and R³ is H, halogen, CN, OH, NH₂, NHCH₃, orOCH₃; or R² is H, halogen, CN, OH, NH₂, NHCH₃, or CH₃, and R3 is H,optionally substituted aryl, optionally substituted heterocycle,optionally substituted heteroaryl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkylamino, optionally substituted dialkylamino,optionally substituted arylamino, optionally substitutedheteroarylamino, optionally substituted heterocycle-amino, optionallysubstituted alkylcarbonylamino, optionally substitutedalkylsulfonylamino, optionally substituted alkylthio, optionallysubstituted alkylsulfonyl, optionally substituted alkoxy, optionallysubstituted hydroxyalkyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycle-oxy,optionally substituted alkylaminocarbonyl, optionally substitutedarylaminocarbonyl, optionally substituted heteroarylaminocarbonyl,optionally substituted heterocycle-aminocarbonyl, or C(O)-(optionallysubstituted heterocycle); R⁴ is optionally substituted morpholine orthiomorpholine; R⁵ is H, F, or Cl; R⁶ is H, F or Cl; M is selected fromthe group consisting of:

R⁷ and R⁸ are, independently, H, or optionally substituted alkyl; or R⁷and R⁸ are joined to form an optionally-substituted heterocyclecontaining 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, 0 or 1 sulfuratom, 0 or 1 S(O) fragment, 0 or 1 S(O)₂ fragment, and 3 to 6 carbonatoms; R⁹ is H or alkyl; R¹⁰ is H or alkyl optionally substituted withOH, NH₂, NHCH₃, N(CH₃)₂, halogen, alkoxy, CF₃, OCF₃, or CN; or R⁹ andR¹⁰ are joined to form an optionally-substituted heterocycle wherein thefragment —R⁹—R¹⁰— is optionally substituted —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,or —CH₂CH₂CH₂CH₂CH₂—; A is CH or C—F; X is N, CH, C—F or C—Cl; Y is N,CH, C—F or C—Cl; and Z is N, CH, C—F, or C—Cl; or a pharmaceuticallyacceptable salt or solvate thereof.
 2. The compound according to claim1, wherein R⁴ is morpholine.
 3. The compound according to claim 1,wherein R⁴ is morpholine substituted by one or more methyl.
 4. Thecompound according to claim 1, wherein R⁴ is:


5. The compound according to claim 1, wherein R⁷ and R⁸ are joined toform an optionally substituted ring containing at least 1 nitrogen atom.6. The compound according to claim 1, wherein R⁷ and R⁸ are joined toform optionally substituted piperidinyl, pyrrolidinyl, azepanyl,piperazinyl, homopiperazinyl, morpholinyl, or thiomorpholinyl.
 7. Thecompound according to claim 1, wherein R⁷ and R⁸ are, independently, Hor alkyl optionally substituted with OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, amino, alkylsulfonyl, alkylthio,alkylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl, oralkylaminosulfonyl.
 8. The compound according to claim 1, wherein R⁷ andR⁸ are, independently, H or alkyl optionally substituted with CH₂OH,CH₂CH₂OH, F, Cl, CN, NH₂, NH(CH₃), N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃,OCH₃, OCF₃, or SO₂CH₃.
 9. The compound according to claim 8, wherein R⁷and R⁸ are joined to form a heterocycle optionally substituted with 1 to3 groups independently selected from the group consisting of OH,halogen, alkoxy, CF₃, OCF₃, CN, alkylamino, dialkylamino, amino,hydroxyalkyl, alkylsulfonyl, alkylthio, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkylcarbonylamino, alkylsulfonylamino,alkylsulfonylalkyl, alkylaminocarbonyl, alkylaminosulfonyl, andcyanoalkyl.
 10. The compound according to claim 9, wherein saidheterocycle is substituted with 1 to 3 groups independently selectedfrom the group consisting of OH, CH₂OH, CH₂CH₂OH, F, Cl, CN, NH₂,NH(CH₃), N(CH₃)₂, CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃,CH₂CN, CH(CH₃)CN, C(CH₃)₂CN, OCH₃, OCF₃, and SO₂CH₃.
 11. The compoundaccording to claim 1, wherein R⁵ and R⁶ are both H.
 12. The compoundaccording to claim 1, wherein R⁷ and R⁸ are both CH₃.
 13. The compoundaccording to claim 1, wherein R² or R³ is of the structure:

wherein: n is 1 to 5; each R¹⁰ is independently selected from the groupconsisting of OH, halogen, alkoxy, CF₃, OCF₃, CN, alkylamino,dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, or cyanoalkyl.
 14. The compound according to claim13, wherein said substituted phenyl is 3- or 4-substituted.
 15. Thecompound according to claim 14, wherein said phenyl is substituted withOH, CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂, CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂,CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN, C(CH₃)₂CN, OCH₃, OCF₃, orSO₂CH₃.
 16. The compound according to claim 1, wherein R² or R³ isoptionally substituted heterocycle or heteroaryl.
 17. The compoundaccording to claim 16, wherein R² or R³ is heteroaryl substituted with 1to 3 R¹¹ groups independently selected from the group consisting of OH,halogen, alkoxy, CF₃, OCF₃, CN, alkylamino, dialkylamino, hydroxyalkyl,alkylsulfonyl, alkylthio, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkylcarbonylamino, alkylsulfonylamino,alkylsulfonylalkyl, alkylaminocarbonyl, alkylaminosulfonyl, andcyanoalkyl.
 18. The compound according to claim 16, wherein R² or R³ isof the formula:

wherein: Z¹ is O, S, or NR¹²; Z² is CH or N; R¹² is absent, H or alkyl;p is 0 to 2; and each R¹¹ is, independently, selected from the groupconsisting of OH, halogen, alkoxy, CF₃, OCF₃, CN, alkylamino,dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, and cyanoalkyl.
 19. The compound according to claim18, wherein R² or R³ is selected from the group consisting of pyrazole,imidazole, pyrrole, thiophene and furan.
 20. The compound according toclaim 18, wherein R² or R³ is selected from the group consisting ofpyrazole and imidazole.
 21. The compound according to claim 18, whereinR² or R³ is substituted with CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂,CH₂N(CH₃)₂, CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN,C(CH₃)₂CN, OCH₃, OCF₃, or SO₂CH₃.
 22. The compound according to claim16, wherein R² or R³ is selected from the group consisting of:

wherein: m is 0 to 4; q is 0 to 3; each R¹⁴ is, independently, selectedfrom the group consisting of OH, halogen, alkoxy, CF₃, OCF₃, CN,alkylamino, dialkylamino, hydroxyalkyl, alkylsulfonyl, alkylthio,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylamino,alkylsulfonylamino, alkylsulfonylalkyl, alkylaminocarbonyl,alkylaminosulfonyl, and cyanoalkyl.
 23. The compound according to claim16, wherein said R² or R³ is selected from the group consisting ofpiperidine, piperazine, morpholine, pyridine, pyrimidine, andpyridazine.
 24. The compound according to claim 23, wherein said R² orR³ is substituted with CH₂OH, CH₂CH₂OH, F, Cl, CN, N(CH₃)₂, CH₂N(CH₃)₂,CH₂CH₂N(CH₃)₂, CONHCH₃, NHCOCH₃, NHSO₂CH₃, CH₂CN, CH(CH₃)CN, C(CH₃)₂CN,OCH₃, OCF₃, or SO₂CH₃.
 25. The compound according to claim 1, which isof formula (II), wherein R¹ is H or F:


26. The compound according to claim 1, which is of formula (III),wherein R¹ is H or F:


27. The compound according to claim 1, which is of formula (IV):


28. The compound according to claim 1, which is of formula (V), whereinR¹ and R⁶ are independently H or F:


29. The compound according to claim 1, which is of formula (VI), whereinone of R⁵ or R⁶ is F:


30. The compound according to claim 1, wherein M is:


31. The compound according to claim 1, wherein M is:


32. The compound according to claim 1 which is selected from the groupconsisting of:N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;N,N-Dimethyl-4-(3-{4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;4-(3-{5-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-N,N-dimethyl-benzamide;1-[4-(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea;4-(3-{4-[8-(3-Hydroxy-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[8-(6-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;2-{4-[3-(4-Dimethylcarbamoyl-phenyl)-ureido]-phenyl}-4-morpholin-4-yl-quinazoline-7-carboxylicacid (2-dimethylamino-ethyl)-amide;4-(3-{2-Fluoro-4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]-ureido}-benzamide;5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylicacid;N,N-dimethyl-4-(3-(4-(7-(5-(4-methylpiperazine-1-carbonyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(5-cyanofuran-2-yl)-4-morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-acetylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide;4-(3-(2,3-difluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-phenyl)-acetamide;1-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)-3-(4-(2-oxopyrrolidin-1-yl)phenyl)urea;4-(3-{4-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N-methyl-benzamide;4-(3-{4-[7-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-(3-{4-[7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;4-(3-{4-[7-(3-Methanesulfonylamino-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;4-(3-{4-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;1-{4-[7-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-{4-[7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-urea;5-(3-{4-[7-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-pyridine-2-carboxylicacid dimethylamide;4-{3-[4-(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl-benzamide;4-{3-[4-(6-Fluoro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl-benzamide;5-(3-{4-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-pyridine-2-carboxylicacid dimethylamide;1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-3-(4-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-quinazolin-2-yl)phenyl)urea;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-urea;4-(3-{4-[7-(5-Methanesulfonyl-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[6-Fluoro-7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[6-Fluoro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7-thiophen-3-yl-quinazolin-2-yl)-phenyl]-urea;4-(3-{4-[6-Fluoro-7-(5-methanesulfonyl-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Methanesulfonyl-phenyl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[8-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Hydroxy-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-(3-{4-[7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}-ureido)-benzamide;N,N-Dimethyl-4-(3-[4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl]-ureido)-benzamide;N-(2-Dimethylamino-ethyl)-N-methyl-4-{3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;4-(3-{4-[7-(3-Hydroxymethyl-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyridin-3-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]-ureido}-benzamide;4-(3-{4-[7-(3-Fluoro-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Methoxy-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Acetylamino-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Dimethylamino-phenyl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-{3-[4-(7-Furan-2-yl-4-morpholin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-thiophen-3-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;4-{3-[4-(7-Furan-3-yl-4-morpholin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl-benzamide;4-(3-{5-[7-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-(3-{5-[7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-benzamide;N-Methyl-4-(3-{4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;N,N-Dimethyl-4-(3-{5-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-pyridin-2-yl}-ureido)-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-pyridin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-quinolin-3-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;4-(3-{4-[7-(6-Methoxy-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;N,N-Dimethyl-4-(3-{4-[7-(5-methyl-thiophen-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;N,N-Dimethyl-4-(3-{4-[7-(4-methyl-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;N-(2-Dimethylamino-ethyl)-N-methyl-4-(3-{4-[7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;4-{3-[4-(7-Benzofuran-2-yl-4-morpholin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-N,N-dimethyl-benzamide;4-(3-{4-[7-(3-Fluoro-pyridin-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(5-Acetylamino-pyridin-3-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-pyrido[3,2-d]pyrimidin-2-yl)-phenyl]-urea;4-(3-{4-[7-(2-Fluoro-pyridin-4-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7-pyridin-4-yl-quinazolin-2-yl)-phenyl]-urea;1-{4-[7-(5-Methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea;N,N-Dimethyl-4-(3-{4-[8-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;N-(2-Dimethylamino-ethyl)-N-methyl-4-{3-[4-(4-morpholin-4-yl-7-pyridin-4-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-{4-[7-(1-methyl-1H-pyrazol-4-yl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}-urea;N,N-Dimethyl-4-{3-[4-(4-morpholin-4-yl-7-thiophen-2-yl-quinazolin-2-yl)-phenyl]-ureido}-benzamide;4-(3-{4-[7-(2-Methoxy-pyrimidin-5-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-{4-[7-(2-Amino-pyrimidin-5-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-(2-(Dimethylamino)acetamido)pyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido]-N,N-dimethyl-benzamide;4-(3-{4-[7-(2-Fluoro-pyridin-3-yl)-4-morpholin-4-yl-pyrido[3,2-d]pyrimidin-2-yl]-phenyl}-ureido)-N,N-dimethyl-benzamide;1-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4-morpholin-4-yl-7-pyrimidin-5-yl-quinazolin-2-yl)-phenyl]-urea;N,N-Dimethyl-4-(3-{4-[7-(furan-2-yl)-4-morpholin-4-yl-quinazolin-2-yl]-phenyl}-ureido)-benzamide;1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(5-(7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)urea;4-(3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)pyridin-2-yl)ureido)-benzamide;N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridazin-4-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-methyl-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;N-methyl-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(4-methylpyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(6-methoxypyridin-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridazin-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyridazin-4-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(4-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(6-fluoro-7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(6-fluoro-7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureidodimethyl-benzamide)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(6-fluoro-7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(6-fluoro-7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(5-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)pyridin-2-yl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(4-methylpyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;5-(3-(2-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethylpicolinamide;5-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethylpicolinamide;5-(3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethylpicolinamide;4-(3-(4-(4-(2,6-dimethylmorpholino)-7-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(4-(2,6-dimethylmorpholino)-7-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(4-(2,6-dimethylmorpholino)-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-5-(3-(5-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)picolinamide;5-(3-(2-fluoro-4-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethylpicolinamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(4-(2,6-dimethylmorpholino)-7-(pyrimidin-5-yl)quinazolin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-4-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(4-(2-methylmorpholino)-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-N,N-dimethyl-4-(3-(5-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)pyridin-2-yl)ureido)-benzamide;3-fluoro-4-(3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-(2-methylmorpholino)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-6-fluoro-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-(2-methylmorpholino)-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-(2-methylmorpholino)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(6-fluoro-7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-hydroxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-(6-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;1-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;4-(3-(5-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;N,N-dimethyl-4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(2-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;3-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(4-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-chloro-4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-N,N-dimethyl-4-(3-(5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-benzamide;3-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(5-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)pyridin-2-yl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(6-aminopyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(6-aminopyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-3-fluoro-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide4-(3-(4-(7-methoxy-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(6,7-dimethoxy-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(7-methoxy-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;1-(4-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;4-(3-(4-(7-(5-((dimethylamino)methyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;N-(2-(dimethylamino)ethyl)-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(7-(4-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-aminopyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(R)-1-(4-(3-aminopyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)urea;N-(2-(dimethylamino)ethyl)-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;1-(4-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-aminopyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(R)-1-(4-(3-aminopyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;1-(2-fluoro-4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;1-(2-fluoro-4-(4-morpholino-7-(pyridin-4-yl)quinazolin-2-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(2-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)urea;4-(3-(2-fluoro-4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N-methyl-benzamide;4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(2-(dimethylamino)ethyl)-4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)-2-fluorophenyl)urea;4-(3-(4-(7-(5-(2-hydroxypropan-2-yl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-cyanofuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-acetylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(2-(dimethylamino)ethyl)-5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxamide;4-(3-(4-(7-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;3-fluoro-4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)-N,N-dimethylfuran-2-carboxamide;4-(3-(4-(7-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)-2-fluorophenyl)ureido)-N,N-dimethyl-benzamide;1-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)-3-(4-(3-hydroxypyrrolidine-1-carbonyl)phenyl)urea;4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N-methyl-benzamide;(S)-1-(4-(3-aminopyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;N-(2-(dimethylamino)ethyl)-4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;N-(2-(dimethylamino)ethyl)-4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N-methyl-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(3-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-2-fluoro-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;5-(3-(3-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethylpicolinamide;4-(3-(4-(7-(3,5-dimethylisoxazol-4-yl)-4-morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(5-(7-(3-(methylsulfonyl)phenyl)-4-morpholino-quinazolin-2-yl)pyridin-2-yl)ureido)-benzamide;4-(3-(3-fluoro-4-(4-(2-methylmorpholino)-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(6-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(3-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;2-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(2-methoxypyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(6-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(2-methylpyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-N,N-dimethyl-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(3-fluoro-4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(3-fluoro-4-(7-(5-(2-hydroxypropan-2-yl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-(dimethylamino)pyrimidin-5-yl)-4-morpholino-quinazolin-2-yl)-3-fluorophenyl)ureido)-N,N-dimethyl-benzamide;2-fluoro-4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2,5-difluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2,3-difluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2,3-difluoro-4-(7-(5-methylfuran-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(2,3-difluoro-4-(7-(furan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(2-((2-hydroxyethyl)amino)pyridin-3-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-((4-hydroxypiperidin-1-yl)methyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(hydroxymethyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;4-(3-(4-(7-(4-(dimethylamino)piperidine-1-carbonyl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;(R)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;(S)-1-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)phenyl)-3-(4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)urea;4-(3-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-4-morpholino-quinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)-acetamide;1-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)-3-(4-(2-oxopyrrolidin-1-yl)phenyl)urea;N-(4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N,N-dimethyl-4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(2-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N,N-dimethyl-4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-benzamide;4-(3-(2-fluoro-4-(7-(6-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-2-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridazin-4-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(3-(methylsulfonyl)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(5-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;N-(4-(3-(5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;4-(3-(4-(7-(5-ethylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;4-(3-(4-(7-(5-(1,2-dihydroxyethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide;N-(4-(3-(4-(7-(5-ethylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-(2-hydroxypropan-2-yl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(pyridazin-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(5-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;N-(4-(3-(5-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;N-(4-(3-(5-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;N-(4-(3-(5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2-yl)pyridin-2-yl)ureido)phenyl)acetamide;N-(4-(3-(4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-ethylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-3-fluorophenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-3-fluorophenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(5-(2-hydroxypropan-2-yl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-ethylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-2-fluorophenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(2-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(6-methylpyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)-2-fluorophenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(6-methoxypyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(5-(hydroxymethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(5-(1-hydroxyethyl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(5-(2-hydroxypropan-2-yl)furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-methyl-N-(4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(5-ethylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(4-(3-(4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(4-(3-(4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-methyl-N-(4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-methyl-N-(4-(3-(4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-methyl-N-(4-(3-(4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(4-(3-(4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(4-(3-(4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(4-(3-(4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-(3-fluoro-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(3-fluoro-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(2-fluoro-4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-methyl-N-(4-(3-(4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-methyl-N-(4-(3-(4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)-N-methylacetamide;N-methyl-N-(4-(3-(4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-methyl-N-(4-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(2-methoxypyrimidin-5-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-2-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(6-fluoro-7-(5-methylfuran-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(6-fluoro-7-(furan-2-yl)-4-morpholinoquinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(6-fluoro-4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(6-fluoro-4-morpholino-7-(pyridin-3-yl)quinazolin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(2-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;N-(4-(3-(3-fluoro-4-(4-morpholino-7-(pyridin-3-yl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide;andN-(4-(3-(3-fluoro-4-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenyl)ureido)phenyl)acetamide.33. The compound according to claim 1 which is a salt of an acid. 34.The compound according to claim 33, wherein said acid is selected fromthe group consisting of acetic, propionic, lactic, citric, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,trifluoroacetic, and camphorsulfonic.
 35. A method for co-regulatingPI3K and mTOR, said method comprising administering a therapeuticallyeffective amount of a compound of claim 1 to a patient in need thereof.36. The method according to claim 35, wherein said co-regulationcomprises inhibition of the PI3K/AKT/mTOR pathway.
 37. A method fortreating a condition treatable by inhibiting the PI3K/AKT/pathway, saidmethod comprising administering a therapeutically effective amount of acompound of claim 1 to a patient in need thereof.
 38. The methodaccording to claim 37, wherein said condition is an inflammatorydisorder.
 39. The method according to claim 38, wherein saidinflammatory disorder is selected from the group consisting ofarthritis, pulmonary fibrosis, myocardial infarction, and peritonitis.40. A method for treating a disease characterized by an abnormalcellular proliferation resulting from a dysregulated PI3K/AKT/mTORpathway, said method comprising administering of a therapeuticallyeffective amount of a compound of claim 1 to a patient in need thereof.41. The method according to claim 40, wherein said disease is cancer.42. The method according to claim 41, wherein said cancer is of theprostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx,pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus,cervix, breast, ovaries, vagina, testicles, skin, thyroid, blood, lymphnodes, kidney, liver, intestines, pancreas, brain, central nervoussystem, adrenal gland, or skin or a leukemia.
 43. The method accordingto claim 42, wherein said cancer is cancer of the prostate.
 44. Themethod according to claim 40, wherein said patient has at least onesolid tumor.
 45. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 46. Akit comprising a compound of claim 1.